Nodulisporic acid derivative spot-on formulations for combating parasites

ABSTRACT

This invention provides for, inter alia, spot-on compositions for the treatment or prophylaxis of parasite infestations in mammals or birds which comprise:  
     (1) at least one nodulisporic acid derivative;  
     (2) an acceptable liquid carrier vehicle; and  
     (3) optionally, a crystallization inhibitor.  
     The invention also provides for a method of treating parasitic infestations or for the prophylaxis of parasite infestations in mammals or birds which comprises topically applying to said mammal or bird an effective amount of a composition according to the present invention. Further, this invention relates to an amidation process to prepare amide derivatives of nodulisporic acid and to intermediate formed in this process.

RELATED APPLICATIONS

[0001] This application claims priority to Provisional Application U.S.S No. 60/415,627 entitled “A Method for the Synthesis ofNodulisporamide” filed Oct. 2, 2002.

[0002] This application Reference is also made to copending applicationU.S. Ser. No. 10/279,356, filed Oct. 24, 2002, which in turn is acontinuation-in-part of application U.S. Ser. No. 10/155,397, filed May24, 2002, now pending, which in turn is a divisional of application Ser.No. 09/376,736, filed Aug. 17, 1999, now U.S. Pat. No. 6,426,333 issuedon Jul. 30, 2002, which in turn is a continuation in-part of applicationU.S. Ser. No. 09/271,470, filed Mar. 17, 1999, now allowed, which inturn is a continuation-in-part of copending International ApplicationPCT/FR97/01548 having an international filing date of Sep. 15, 1997, anddesignating the U.S. and claiming priority from French Application No.96/11446, filed Sep. 19, 1996. Reference is also made to: U.S.application Ser. Nos. 10/052,597, filed Jan. 17, 2002, Ser. No.10/120,691, filed Apr. 11, 2002, Ser. No. 08/719,942, filed Sep. 25,1996, Ser. No. 08/692,430, filed Aug. 5, 1996, Ser. No. 08/863,182,filed May 27, 1997, Ser. No. 08/692,113, filed Aug. 5, 1996, Ser. No.08/863,392, filed May 27, 1997, and Ser. No. 08/891,047, filed Jul. 10,1997; French Application No. 97 03709, filed Mar. 26, 1997; andPCT/FR98/00601. All of the above-mentioned applications, as well as alldocuments cited therein, including parent applications if available, anddocuments referenced or cited in documents cited herein, are herebyincorporated herein by reference.

FIELD OF THE INVENTION

[0003] This invention relates to inter alia spot-on formulations forcombating parasites in birds and mammals. In particular, this inventionprovides for spot-on formulations comprising a composition comprising atleast one nodulisporic acid derivative and a pharmaceutically orveterinary acceptable liquid carrier vehicle. This invention alsoprovides for an improved method for eradicating, controlling, andpreventing parasite infestation in birds and mammals. Further, thisinvention relates to an amidation process to prepare amide derivativesof nodulisporic acid and to intermediates formed in the process.

BACKGROUND OF THE INVENTION

[0004] Animals such as mammals and birds are often susceptible toparasite infestations. These parasites may be ectoparasites, such asinsects, and endoparasites such as filariae and worms.

[0005] Domesticated animal, such as cats and dogs, are often infestedwith one or more of the following ectoparasites:

[0006] cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp. andthe like),

[0007] ticks (R^(h)ipicephalus sp., Ixodes sp., Dermacentor sp.,Amblyomma sp. and the like), and

[0008] mites (Demodex sp., Sarcoptes sp., Otodectes sp. and the like),

[0009] lice (Trichodectes sp., Cheyletiella sp., Lignonathus sp., andthe like), and

[0010] flies (Hematobia sp., Musca sp., Stomoxys sp., Dermatobia sp.,Coclyomia sp., and the like).

[0011] Fleas are a particular problem because not only do they adverselyaffect the health of the animal or human, but they also cause a greatdeal of psychological stress. Moreover, fleas are also vectors ofpathogenic agents in animals, such as dog tapeworm (Dipylidium caninum),and humans.

[0012] Similarly, ticks are also harmful to the physical andpsychological health of the animal or human. However, the most seriousproblem associated with ticks is that they are the vector of pathogenicagents, agents which cause diseases in both humans and animal. Majordiseases which are caused by ticks include borreliosis (Lyme diseasecaused by Borrelia burgdorferi), babesiosis (or piroplasmosis caused byBabesia sp.) and rickettsiosis (also known as Rocky Mountain spottedfever). Ticks also release toxins which cause inflammation or paralysisin the host. Occasionally, these toxins are fatal to the host, such asin the case of the Australian paralysis tick, Ixodes holocyclus.

[0013] Moreover, mites and lice are particularly difficult to combatsince there are very few active substances which act on these parasitesand they require frequent treatment.

[0014] Likewise, farm animals are also susceptible to parasiteinfestations. For example, cattle are affected by a large number ofparasites. Likewise, arthropod pests, such as flea, lice and ticks,infest poultry. A parasite, which is very prevalent among farm animals,is a tick genus Boophilus, especially those of the species microplus(cattle tick), decoloratus and anulatus. Ticks, such as Boophilusmicroplus, are particularly difficult to control because they live inthe pasture where the farm animals graze. Other important parasites ofcattle and sheep are listed as follows in order of decreasingimportance:

[0015] myiases such as Dermatobia hominis (known as Berne in Brazil) andCochlyomia hominivorax (greenbottle); sheep myiases such as Luciliasericata, Lucilia cuprina (known as blowfly strike in Australia, NewZealand and South Africa). These are flies whose larva constitutes theanimal parasite;

[0016] flies proper, namely those whose adult constitutes the parasite,such as Haematobia irritans (horn fly);

[0017] lice such as Linognathus vitulorum, etc.; and

[0018] mites such as Sarcoptes scabiei and Psoroptes ovis.

[0019] The above list is not exhaustive and other ectoparasites are wellknown in the art to be harmful to animals and humans. These include, forexample migrating dipterous larvae.

[0020] Animals and humans also suffer from endoparasitical infectionsincluding, for example, helminthiasis, which is most frequently causedby a group of parasitic worms described as nematodes or roundworms.These parasites cause severe economic losses in pigs, sheep, horses, andcattle as well as affecting other domestic animals, such as dogs, catsand poultry. Other parasites which occur in the gastrointestinal tractof animals and humans include Ancylostoma, Anecator, Ascaris,Strongyloides, Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris,Enterobius and parasites which are found in the blood or other tissuesand organs such as filarial worms and the extra intestinal stages ofStrogyloides, Toxocara and Trichinella.

[0021] Many insecticides exist in the art for treating parasites. Theseinsecticides vary in their effectiveness to a particular parasite aswell as their cost. However, the results of these insecticides is notalways satisfactory because of, for example, the development ofresistance by the parasite to the therapeutic agent, as is the case, forexample, with carbamates, organophosphorus compounds and pyrethroids.Moreover, there is at the present time no truly effective method forcontrolling the set of parasites indicated above. Thus, there is a needin the art for more effective antiparasitic formulation treatment andprotection of animal, e.g. mammals, fish and birds for a wide range ofparasites. Moreover, there is a need in the art for an antiparasiticformulation which is easy to use on any type of domestic animal,irrespective of its size and the nature of its coat and which do notneed to be sprinkled over the entire body of the mammal, fish or bird.Further, the formulation should be effective for a long period of timethereby reducing the number of times it has to be applied.

[0022] Compounds, which exhibit a degree of activity against a widerange ectoparasites, are known in the art. The arylpyrazoles as a classare known in the art and are described, for example, in copendingapplications U.S. Ser. No. 07/719,942; 08/933,016; 09/174,598;08/863,182; and 08/863,692, as well as in U.S. Pat. No. 5,576,429; U.S.Pat. No. 5,122,530, EP-A-295,217, EP-A-352,944 and EP 295 177, thedisclosures of which, as well as the references cited herein, areincorporated by reference. Reference is made to, for example, U.S. Pat.No. 5,567,429, U.S. Pat. No. 5,122,530, EP 295,117, and EP 846,686 A1(or Banks GB 9,625,045, filed Nov. 30, 1996 also believed to beequivalent to U.S. Ser. No. 309,229, filed Nov. 17, 1997). This class ofinsecticides is known to possess excellent activity against insects,such as ticks and fleas. Fipronil is a 1-N-aryl pyrazole that isparticularly effective against fleas and ticks

[0023] Other compounds parasiticides that are know in the art to beeffective are those which possess a macrocyclic lactone ring. Thesecompounds are particularly effective against ectoparasites, includinglice, blowflies, flies, mosquitoes, mites, migrating dipterous larvae,and ticks, as well as endoparasites, such as nematodes and roundworms.Compounds of this group include avermectins, milbemycins, andderivatives of these compounds, for example, ivermectin or emamectin.Such substances are described, for example, in U.S. Pat. Nos. 3,950,360;4,199,569; 4,879,749; and 5,268,710.

[0024] These compounds are well known to a person skilled in the art andare easily obtained either commercially or through techniques know inthe art. Reference is made to the widely available technical andcommercial literature. For avermectins, ivermectin and abamectin,reference may be made, for example, to the work “Ivermectin andAbamectin”, 1989, by M. H. Fischer and H. Mrozik, William C. Campbell,published by Springer Verlag., or Albers-Schönberg et al. (1981),“Avermectins Structure Determination”, J. Am. Chem. Soc., 103,4216-4221. For doramectin, “Veterinary Parasitology”, vol. 49, No. 1,Jul. 5-15, 1993, may in particular be consulted. For milbemycins,reference may be made, inter alia, to Davies H. G. et al., 1986,“Avermectins and Milbemycins”, Nat. Prod. Rep., 3, 87-121, Mrozik H. etal., 1983, Synthesis of Milbemycins from Avermectins, Tetrahedron Lett.,24, 5333-5336, U.S. Pat. No. 4, 134, 973 and EP 677,054. These compoundsare either natural products or are semi-synthetic derivatives thereof.The structure of these compounds is closely related, e.g., by sharing acomplex 16-member macrocyclic lactone ring. The natural productavermectins are disclosed in U.S. Pat. No. 4,310,519 toAlbers-Schönberg, et al., and the 22,23-dihydro avermectin compounds aredisclosed in Chabala, et al., U.S. Pat. No. 4,199,569. Mention is alsomade of Kitano, U.S. Pat. No. 4,468,390, Beuvry et al., U.S. Pat. No.5,824,653, European Patent Application 0 007 812 A1, published Jun. 2,1980, U.K. Patent Specification 1 390 336, published Apr. 9, 1975,European Patent Application 0 002 916 A2, and Ancare New Zealand PatentNo. 237 086, inter alia. Naturally occurring milbemycins are describedin Aoki et al., U.S. Pat. No. 3,950,360 as well as in the variousreferences cited in “The Merck Index” 12^(th) ed., S. Budavari, Ed.,Merck & Co., Inc. Whitehouse Station, N.J. (1996). Semisyntheticderivatives of these classes of compounds are well known in the art andare described, for example, in U.S. Pat. No. 5,077,308, U.S. Pat. No.4,859,657, U.S. Pat. No. 4,963,582, U.S. Pat. No. 4,855,317, U.S. Pat.No. 4,871,719, U.S. Pat. No. 4,874,749, U.S. Pat. No. 4,427,663, U.S.Pat. No. 4,310,519, U.S. Pat. No. 4,199,569, U.S. Pat. No. 5,055,596,U.S. Pat. No. 4,973,711, U.S. Pat. No. 4,978,677, U.S. Pat. No.4,920,148 and EP 667 054.

[0025] Other classes of compounds include insect growth regulating (IGR)compounds, which either mimic juvenile hormones or the inhibit synthesisof chintin. IGR compounds that mimic juvenile hormones include, forexample, azadirachtin, diofenolan, fenoxycarb, hydroprene, kinoprene,methoprene, pyriproxyfen, tetrahydroazadirachtin, and4-chloro-2-(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridizine-3(2H)-one.Chintin-synthesis inhibitors include, for example, chlorfluazuron,cyromazine, diflubenzuron, fluazuron, flucycloxuron, flufenoxuron,hexaflumuron, lufenuron, tebufenozide, teflubenzuron, triflumuron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylurea,and 1-(2,6-difluorobenzoyl) -3-(2-fluoro-4-trifluoro-methyl)phenylurea.

[0026] Another class of compounds, which are know in the art as potentendo- and ectoantiparasitic agents, are nodulisporic acid derivatives.These compounds are based upon three structures, A, B or C, which havethe following structures:

[0027] nodulisporic acid (compound A)

[0028]  29,30-dihydro-20,30-oxa-nodulisporic acid (compound B)

[0029] and

[0030] 31-hydroxy-20,30-oxa-29,30,31,32-tetrahydro-nodulisporic acid(compound C)

[0031] These compounds were obtained from the fermentation culture ofNodulisporium sp. MF-5954 (ATCC 74245) and the isolation andpurification of the three nodulisporic acids are disclosed in U.S. Pat.No. 5,399,582. Derivatives of these compounds are described in WO96/29073 and U.S. Pat. Nos. 5,945,317; 5,962,499; 5,834,260; 6,399,796;6,221,894; 6,136,838; 5,595,991; and 5,614,546.

[0032] Nodulisporic acid derivatives possess potent activity againstparasites, particularly helminths, ectoparasites, insects, and acarides,infecting man, animals and plants. These compounds have utility in humanand animal health, agriculture and pest control in household andcommercial areas.

[0033] The disease or group of diseases described generally ashelminthiasis is due to infection of an animal host with parasitic wormsknown as helminths. Helminthiasis is a prevalent and serious economicproblem in domesticated animals such as swine, sheep, horses, cattle,goats, dogs, cats, fish, buffalo, camels, llamas, reindeer, laboratoryanimals, furbearing animals, zoo animals and exotic species and poultry.Among the helminths, the group of worms described as nematodes causeswidespread and often times serious infection in various species ofanimals. The most common genera of nematodes infecting the animalsreferred to above are Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia,Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Habronema,Druschia, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma,Uncinaria, Toxascaris and Parascaris. Certain of these, such asNematodirus, Cooperia, and Oesophagostomum attack primarily theintestinal tract while others, such as Haemonchus and Ostertagia, aremore prevalent in the stomach while still others such as Dictyocaulusare found in the lungs. Still other parasites may be located in othertissues and organs of the body such as the heart and blood vessels,subcutaneous and lymphatic tissue and the like. The parasitic infectionsThe parasitic infections known as helminthiases lead to anemia,malnutrition, weakness, weight loss, severe damage to the walls of theintestinal tract and other tissues and organs and, if left untreated,may result in death of the infected host. The compounds of thisinvention have activity against these parasites, and in addition arealso active against Dirofilaria in dogs and cats, Nematospiroides,Syphacia, Aspiculuris in rodents, arthropod ectoparasites of animals andbirds such as ticks, mites such as scabies lice, fleas, blowflies, andother biting insects in domesticated animals and poultry, such asTenophalides, Ixodes, Psoroptes, and Hemotobia, in sheep Lucilia sp.,biting insects and such migrating dipterous larvae as Hypoderma sp. incattle, Gasterophilus in horses, and Cuterebra sp. in rodents andnuisance flies including blood feeding flies and filth flies.

[0034] Nodulisporic acid derivatives are also useful against parasiteswhich infect mammals, such as cats, dogs and humans. The most commongenera of parasites of the gastrointestinal tract of man areAncylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria,Trichuris, and Enterobius. Other medically important genera of parasiteswhich are found in the blood or other tissues and organs outside thegastrointestinal tract are the filiarial worms such as Wuchereria,Brugia, Onchocerca and Loa, Dracunuculus and extra intestinal stages ofthe intestinal worms Strongyloides and Trichinella. The compounds arealso of value against arthropods parasitizing man, biting insects andother dipterous pests causing annoyance to man.

[0035] Nodulisporic acid derivatives are also active against householdpests such as the cockroach, Blatella sp., clothes moth, Tineola sp.,carpet beetle, Attagenus sp., the housefly Musca domestica as well asfleas, house dust mites, termites and ants.

[0036] Nodulisporic acid derivatives are also useful against insectpests of stored grains such as Tribolium sp., Tenebrio sp. and ofagricultural plants such as aphids, (Acyrthiosiphon sp.); againstmigratory orthopterans such as locusts and immature stages of insectsliving on plant tissue. The compounds are useful as a nematocide for thecontrol of soil nematodes and plant parasites such as Meloidogyne sp.,which may be of importance in agriculture. The compounds are also highlyuseful in treating acreage infested with fire and nests. The compoundsare scattered above the infested area in low levels in bait formulationswhich are brought back to the nest. In addition to a direct-but-slowonset toxic effect on the fire ants, the compound has a long-term effecton the nest by sterilizing the queen which effectively destroys thenest.

[0037] Nodulisporic acid and its derivatives are also effective againstarthropod pests, for example fleas, ticks, ice and other biting insectsin domesticated animals and poultry, such as Ctenophalides, Ixodes,Psoroptes, Lucilia and Hematobia.

[0038] It is known to combine the above-mentioned classes of compoundsin order to achieve a broader spectrum of activity or, in some instancessynergy. For example, U.S. Pat. No. 5,945,317 discloses co-administeringnodulisporic acid derivatives with avermectin or milbemycins, or otherantihelmintic agents, such as morantel, pyrantel, or febantel, orbenzimidizoles, such as thiabendazole or cambendazole. Other agentsdescribed therein include IGR compounds, such as lufenuron, or1-N-arylpyrazoles, such a fipronil. See also, U.S. Pat. No. 5,962,499and 6,221,894. While it is known in the art that it is sometimespossible to combine various parasiticides in order to broaden theantiparasitical spectrum, it is not possible to predict, a priori, whichcombinations will work for a particular animal or disease state. Forthis reason, the results of various combinations is not alwayssuccessful and there is a need in the art for more effectiveformulations which may be easily administered to the animal.

[0039] Various methods of formulating antiparasitical formulations areknown in the art. These include oral formulations, baits, dietarysupplements, powders, shampoos, etc. Formulations for localized topicalapplications of antiparasitical formulations are also known in the art.For example, pour-on solutions comprising 1-N-phenylpyrazoles, such asfipronil, are known in the art and are described in copendingapplication Ser. No. 08/933,016, herein incorporated by reference. Othermethods for formulating antiparasitic agents include spot-onformulations.

[0040] Spot-on formulations are well known techniques for topicallydelivering an antiparasitic agent to a limited area of the host. Forexample, U.S. Pat. No. 5,045,536 describes such formulations forectoparasites. Moreover, it is generally known in the art to formulateavermectin and milbemycin derivatives as spot-on formulations. See, e.g.U.S. Pat. No. 5,045,536; EP 677,054; U.S. Pat. No. 5,733,877; U.S. Pat.No. 5,677,332; U.S. Pat. No. 5,556,868; and U.S. Pat. No. 5,723,488.U.S. Pat. Nos. 5,962,499 and 5,595,998 generally discusses formulatingnodulisporic acid derivatives as pour-on or spot-on formulations, withor without additional antiparasitic agents. However, as discussed inU.S. Pat. No. 5,045,536, a large number of solvent systems described inthe art provide formulations for localized topical application whichcause irritancy or toxicity to the host as well as being effective for along period of time. Hence, there is a need in the art both for moreeffective for a longer period of time and less irritant or toxicformulations. Thus, there is a need in the art for a spot-onformulation, which is effective over a long period of time against awide range of endoparasites and ectoparasites in birds and mammals.

SUMMARY OF THE INVENTION

[0041] The invention provides inter alia for spot-on formulations forthe treatment or prophylaxis of endoparasites of mammals, fish andbirds, and in particular, cats, dogs, horses, chickens, sheep and cattlewith the aim of ridding these hosts of all the parasites commonlyencountered by birds and mammals. The invention also provides foreffective and lasting destruction of ectoparasites, such as fleas,ticks, mites, e.g. itch mites, mosquitoes, flies and lice. Further, thespot-on formulations retain their efficacy over a long period of time,thereby reducing the number of applications of the formulation to theanimal.

[0042] In particular this invention provides for spot-on formulationsfor the treatment or prophylaxis of parasite infestations in mammals orbirds, which comprise:

[0043] (1) a composition comprising an effective amount of at least onenodulisporic acid derivative;

[0044] (2) a pharmaceutically or veterinary liquid carrier vehicle; and

[0045] (3) optionally, a crystallization inhibitor.

[0046] The invention also provides for an easy method of treatingparasitic infestations or for the prophylaxis of parasite infestationsin mammals or birds which comprises topically applying to said mammal orbird an effective amount of a formulation according to the presentinvention.

[0047] This invention further provides for formulations which, whenapplied locally, will diffuse over the entire body of the host and thendry, without crystallizing, and which do not affect the appearance ofthe coat after drying by, for example, leaving crystals or making thecoat sticky. This has the further advantage in animals which groomthemselves of not being orally ingested, where the therapeutic agentmight not be well tolerated orally or might interact with othertherapeutic agents.

[0048] The very high effectiveness of the method and of the formulationsaccording to the invention provides not only for a high instantaneouseffectiveness but also for an effectiveness of very long duration afterthe treatment of the animal.

[0049] This invention further provides for an amidation process toprepare amide derivatives of nodulisporic acid in higher yield withbetter purity. Novel intermediates in this process also form a part ofthis invention.

[0050] In this disclosure and in appended claims, terms such as“comprising” and “comprises” and the like, have the meanings ascribed tothem in U.S. Patent Case Law. The terms “comprises” and “comprising” areopen-ended and allow for the inclusion of additional ingredients orsteps.

[0051] Clearly, a spot-on formulation spot-on comprising at least onenodulisporic acid derivative, advantageously t-butyl nodulisporamide ina veterinary acceptable liquid carrier vehicle is a basic or novelfeature of the herein invention, as well as methods for preventing ortreating parasites on an animal, e.g., dog, cat, by applying theformulation, e.g., monthly, and methods for preparing the formulations,e.g., by administering the ingredients, are also novel and basicfeatures of the invention. That the invention performs as hereindescribed is surprising, unexpected and nonobvious.

[0052] These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

[0053] This invention provides for a spot-on formulation for thetreatment and prophylaxis of parasite infestation in mammals or birdswhich comprises

[0054] (1) an effective amount of at least one nodulisporic acidderivative

[0055] (2) a pharmaceutically or veterinary acceptable liquid carriervehicle; and

[0056] (3) optionally, a crystallization inhibitor

[0057] More especially preferred are spot-on formulations comprising:

[0058] (1) an effective amount of at least one nodulisporic acidderivative;

[0059] (2) a liquid carrier vehicle comprises a solvent and optionally acosolvent wherein the solvent is selected from the group consisting ofacetone, acetonitrile, benzyl alcohol, butyl diglycol,dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, diethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethyleneglycol monoethyl ether, ethylene glycol, diethyl phthalate fatty acidesters, such as the diethyl ester or diisobutyl adipate, and a mixtureof at least two of these solvents and the cosolvent is selected from thegroup consisting of absolute ethanol, isopropanol or methanol; and

[0060] (3) optionally, a crystallization inhibitor selected from thegroup consisting of an anionic surfactant, a cationic surfactant, anon-ionic surfactant, an amine salt, an amphoteric surfactant orpolyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodiumcarboxymethylcellulose, and acrylic derivatives, or a mixture of thesecrystallization inhibitors.

[0061] This invention includes all nodulisporic acid derivatives know inthe art, including all steroisomers, such as those described in theprior publication described above, which are expressly incorporated byreference. Especially preferred are spot-on formulations comprisingnordulisporic acid derivatives of the formula:

[0062] wherein

[0063] R¹ is (1) hydrogen,

[0064] (2) optionally substituted alkyl,

[0065] (3) optionally substituted alkenyl,

[0066] (4) optionally substituted alkynyl,

[0067] (5) optionally substituted cycloalkyl,

[0068] (6) optionally substituted cycloalkenyl,

[0069] where the substituents on the alkyl, alkenyl, alkynyl, cycloalkyland cycloalkenyl are 1 to 3 groups independently selected from

[0070] (i) alkyl,

[0071] (ii) alkyl, where X is O or S(O)_(m).

[0072] (iii) cycloalkyl,

[0073] (iv) hydroxy,

[0074] (v) halogen,

[0075] (vi) cyano,

[0076] (vii) carboxy,

[0077] (viii) NY Y², where Y¹ and Y² are independently H or alkyl,

[0078] (ix) alkanoylamino, and

[0079] (x) aroylamino wherein said aroyl is optionally substituted with1 to 3 groups independently selected from R^(f)

[0080] (7) aryl or arylalkyl, wherein said aryl is optionallysubstituted with 1 to 3 groups independently selected from R^(f),

[0081] (8) perfluoroalkyl

[0082] (9) a 5- or 6-member heterocycle containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogenatoms optionally substituted by 1 to 3 groups independently selectedfrom hydroxy, oxo, alkyl and halogen, and which may be saturated orpartly unsaturated,

[0083] R₂, R₃, and R₄ are independently OR^(a), OCO₂R^(b),OC(O)NR^(c)R^(d); or

[0084] R₁ and R₂ represent ═O, ═NOR^(a) or ═N—NR^(c)R^(d);

[0085] R₅ and R₆ are H; or

[0086] R₅ and R₆ together represent —O—;

[0087] R₇ is (1) CHO, or

[0088] (2), the fragment

[0089] R₈ is (1) H,

[0090] (2) OR^(a), or

[0091] (3) NR^(c)R^(d)

[0092] R₉ is (1) H, or

[0093] (2) OR^(a);

[0094] R₁₀ is (1) CN,

[0095] (2) C(O)OR^(b),

[0096] (3) C(O)N(OR^(b))R^(c),

[0097] (4) C(O)NR^(c)R^(d),

[0098] (5) NHC(O)OR^(b),

[0099] (6) NHC(O)NRCR^(d),

[0100] (7) CH₂OR^(a),

[0101] (8) CH₂OCO₂R^(b),

[0102] (9) CH₂OC(O)NR^(c)R^(d),

[0103] (10) C(O)NR^(c)NR^(c)R^(d), or

[0104] (11) C(O)NR^(c)SO₂R^(b);

[0105]

represents a single or a double bond;

[0106] R^(a) is (1) hydrogen,

[0107] (2) optionally substituted alkyl,

[0108] (3) optionally substituted alkenyl,

[0109] (4) optionally substituted alkynyl,

[0110] (5) optionally substituted alkanoyl,

[0111] (6) optionally substituted alkenoyl,

[0112] (7) optionally substituted alkynoyl,

[0113] (8) optionally substituted aroyl,

[0114] (9) optionally substituted aryl,

[0115] (10) optionally substituted cycloalkanoyl,

[0116] (11) optionally substituted cycloalkenoyl,

[0117] (12) optionally substituted alkylsulfonyl

[0118] (13) optionally substituted cycloalkyl

[0119] (14) optionally substituted cycloalkenyl

[0120] where the substituents on the alkyl, alkenyl, alkynyl, alkanoyl,alkenoyl, alkynoyl, aroyl, aryl, cycloalkanoyl, cycloalkenoyl,alkylsulfonyl, cycloalkyl and cycloalkenyl are from 1 to 10 groupsindependently selected from hydroxy, alkoxy, cycloalkyl, arylalkoxy,NR^(g)R^(h), CO₂R_(b), CONR^(c)R^(d) and halogen,

[0121] (15) perfluoroalkyl,

[0122] (16) arylsulfonyl optionally substituted with 1 to 3 groupsindependently selected from alkyl, perfluoroalkyl, nitro, halogen andcyano,

[0123] (17) a 5- or 6-member heterocycle containing 1 to 4 heteroatomsselected from oxygen, sulfur and nitrogen optionally substituted by 1 to4 groups independently selected from alkyl, alkenyl, perfluoroalkyl,amino, C(O)NR^(c)R^(d), cyano, CO₂R^(b) and halogen, and which may besaturated or partly unsaturated;

[0124] R¹ is (1) H,

[0125] (2) optionally substituted aryl,

[0126] (3) optionally substituted alkyl,

[0127] (4) optionally substituted alkenyl,

[0128] (5) optionally substituted alkynyl,

[0129] (6) optionally substituted cycloalkyl,

[0130] (7) optionally substituted cycloalkenyl, or

[0131] (8) optionally substituted

[0132] heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen; where the substituents on thearyl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, or alkynylare from 1 to 10 groups independently selected from

[0133] (i) hydroxy,

[0134] (ii) alkyl,

[0135] (iii) oxo,

[0136] (iv) SO₂NR^(g)R^(h),

[0137] (v) arylalkoxy,

[0138] (vi) hydroxyalkyl,

[0139] (vii) alkoxy,

[0140] (viii) hydroxyalkoxy,

[0141] (ix) aminoalkoxy,

[0142] (x) cyano,

[0143] (xi) mercapto,

[0144] (xii) alkyl-S(O)_(m),

[0145] (xiii) cycloalkyl optionally substituted

[0146] with 1 to 4 groups independently selected from R^(e),

[0147] (xiv) cycloalkenyl,

[0148] (xv) halogen,

[0149] (xvi) alkanoyloxy,

[0150] (xvii) C(O)NR^(g)R^(h),

[0151] (xviii) CO₂R^(i),

[0152] (xix) formyl,

[0153] (xx) —NR^(g)R^(h)

[0154] (xxi) 5 to 9-member heterocycle, which may be saturated orpartially unsaturated, containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen, and optionally substitutedwith 1 to 5 groups independently selected from R^(e),

[0155] (xxii) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e),

[0156] (xxiii) optionally substituted arylalkoxy,

[0157] wherein the aryl substituents are 1,2-methylenedioxy or 1 to 5groups independently selected from R^(e), and

[0158] (xxiv) perfluoroalkyl;

[0159] R^(c) and R^(d) are independently selected from R^(b); or

[0160] R^(c) and R^(d) together with the N to which they are attachedform a 3- to 10-member ring containing 0 to 2 additional heteroatomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(g), hydroxy, thioxo and oxo;

[0161] R^(e) is (1) halogen,

[0162] (2) alkyl,

[0163] (3) perfluoroalkyl,

[0164] (4) —S(O)_(m)R^(i),

[0165] (5) cyano,

[0166] (6) nitro,

[0167] (7) R₁₀(CH₂)_(v)—,

[0168] (8) R^(i)CO₂(CH₂)_(v)—,

[0169] (9) R^(i)OCO(CH₂)_(v)—,

[0170] (10) optionally substituted aryl where the substituents are from1 to 3 of halogen, alkyl, alkoxy, or hydroxy,

[0171] (11) SO₂NR^(g)R^(h), or

[0172] (12) amino;

[0173] R^(f) is (1) alkyl,

[0174] (2) X—C₁-C₄ alkyl, where X is O or S(O)_(m),

[0175] (3) alkenyl,

[0176] (4) alkynyl,

[0177] (5) perfluoroalkyl,

[0178] (6) NY¹Y², where Y¹ and Y² are independently H or alkyl,

[0179] (7) hydroxy,

[0180] (8) halogen, and

[0181] (9) alkanoylamino,

[0182] R^(g) and R^(h) are independently

[0183] (1) hydrogen,

[0184] (2) alkyl optionally substituted with hydroxy, amino, or CO₂R^(i)

[0185] (3) aryl optionally substituted with halogen, 1,2-methylenedioxy,alkoxy, alkyl or perfluoroalkyl,

[0186] (4) arylalkyl, wherein the aryl is optionally substituted withperfluorolkyl or 1,2-methylenedioxy;

[0187] (5) alkoxycarbonyl,

[0188] (6) alkanoyl,

[0189] (7) alkanoylalkyl,

[0190] (9) aryl alkoxycarbonyl,

[0191] (10) aminocarbonyl,

[0192] (11) monoalkylaminocarbonyl

[0193] (12) dialkylaminocarbonyl; or

[0194] R^(g) and R^(h) together with the N to which they are attachedform a 3- to 7-member ring containing 0 to 2 additional heteroatomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(e) and oxo;

[0195] R^(i) is (1) hydrogen,

[0196] (2) perfluoroalkyl,

[0197] (3) alkyl,

[0198] (4) optionally substituted aryl or arylalkyl, where the arylsubstituents are from 1 to 3 groups independently selected from halogen,alkyl, alkoxy, and hydroxy;

[0199] m is 0 to 2; and

[0200] v is 0 to 3; or

[0201] a pharmaceutically acceptable salt thereof.

[0202] In a preferred embodiment, the present invention providescompounds of Formula I wherein

[0203] R₁ is (1) hydrogen,

[0204] (2) optionally substituted alkyl,

[0205] (3) optionally substituted alkenyl,

[0206] (4) optionally substituted alkynyl,

[0207] (5) optionally substituted cycloalkyl,

[0208] (6) optionally substituted cycloalkenyl where the substituents onthe alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl are 1 to 3groups independently selected from

[0209] (i) alkyl,

[0210] (ii) X—C₁-C₆ alkyl, where X is O or S(O)_(m),

[0211] (iii) cycloalkyl,

[0212] (iv) hydroxy,

[0213] (v) halogen,

[0214] (vi) cyano,

[0215] (vii) carboxy, and

[0216] (viii) NY¹Y², where Y¹ and Y² are independently H or alkyl,

[0217] (7) aryl or arylalkyl wherein said aryl is optionally substitutedwith 1 to 3 groups independently selected from R^(f),

[0218] (8) perfluoroalkyl,

[0219] (9) a 5- or 6-member heterocycle containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogenatoms optionally substituted by 1 to 3 groups independently selectedfrom hydroxy, oxo, alkyl and halogen, and which may be saturated orpartly unsaturated,

[0220] R₈ is (1) H,

[0221] (2) OH, or

[0222] (3) NH₂;

[0223] R₉ is (1) H or

[0224] (2) OH;

[0225] R₁₀ is (1) C(O)OR^(b),

[0226] (2) C(O)N(OR^(b))R^(c),

[0227] (3) C(O)NR^(c)R^(d),

[0228] (4) NHC(O)OR^(b),

[0229] (5) NHC(O)NR^(c)R^(d),

[0230] (6) CH₂OR^(a),

[0231] (7) CH₂OCO₂R^(b),

[0232] (8) CH₂OC(O)NR^(c)R^(d),

[0233] (9) C(O)NR^(c)NR^(c)R^(d), or

[0234] (10) C(O)NR^(c)SO₂R^(b);

[0235] R^(a) is (1) hydrogen,

[0236] (2) optionally alkyl,

[0237] (3) optionally substituted alkenyl,

[0238] (4) optionally substituted alkynyl,

[0239] (5) optionally substituted alkanoyl,

[0240] (6) optionally substituted alkenoyl,

[0241] (7) optionally substituted alkynoyl,

[0242] (8) optionally substituted aroyl,

[0243] (9) optionally substituted aryl,

[0244] (10) optionally substituted cycloalkanoyl,

[0245] (11) optionally substituted cycloalkenoyl,

[0246] (12) optionally substituted alkylsulfonyl

[0247] (13) optionally substituted cycloalkyl

[0248] (14) optionally substituted cycloalkenyl where the substituentson the alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl, alkynoyl, aroyl,aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl, cycloalkyl andcycloalkenyl are from 1 to 10 groups independently selected fromhydroxy, alkoxy, cycloalkyl, aryl alkoxy, NR^(g)R^(h), CO₂R^(b),CONR^(c)R^(d) and halogen,

[0249] (15) perfluoroalkyl,

[0250] (16) arylsulfonyl optionally substituted with 1 to 3 groupsindependently selected from alkyl, perfluoroalkyl, halogen and cyano,

[0251] (17) a 5- or 6-member heterocycle containing 1 to 4 heteroatomsselected from oxygen, sulfur and nitrogen optionally substituted by 1 to4 groups independently selected from alkyl, alkenyl, perfluoroalkyl,amino, C(O)NR^(c)R^(d), cyano, CO₂R^(b) and halogen, and which may besaturated or partly unsaturated;

[0252] R^(b) is (1) H,

[0253] (2) optionally substituted aryl,

[0254] (3) optionally substituted alkyl,

[0255] (4) optionally substituted alkenyl,

[0256] (5) optionally substituted alkynyl,

[0257] (6) optionally substituted cycloalkyl,

[0258] (7) optionally substituted cycloalkenyl, or

[0259] (8) optionally substituted 5- to 10-member

[0260] heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen; where the substituents on thearyl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, or alkynylare from 1 to 10 groups independently selected from

[0261] (i) hydroxy,

[0262] (ii) C₁-C₃ alkyl,

[0263] (iii) oxo,

[0264] (iv) SO₂NR^(g)R^(h),

[0265] (v) aryl alkoxy,

[0266] (vi) hydroxy alkyl,

[0267] (vii) alkoxy,

[0268] (viii) hydroxyalkoxy,

[0269] (ix) aminoalkoxy,

[0270] (x) cyano,

[0271] (xi) perfluoroalkyl,

[0272] (xii) alkyl-S(O)_(m),

[0273] (xiii) cycloalkyl optionally substituted

[0274] with 1 to 4 groups independently selected from R^(e),

[0275] (xiv) cycloalkenyl,

[0276] (xv) halogen,

[0277] (xvi) alkanoyloxy,

[0278] (xvii) C(O)NR^(g)R^(h),

[0279] (xviii) CO₂R^(i),

[0280] (xix) optionally substituted arylalkoxy,

[0281] wherein the aryl substituents are 1,2-methylenedioxy or 1 to 5groups independently selected from R^(e),

[0282] (xx) —NR^(g)R^(h),

[0283] (xxi) 5 to 6-member heterocycle, which may be saturated orpartially unsaturated, containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen, and optionally substitutedwith 1 to 5 groups independently selected from R^(e), and

[0284] (xxii) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e);

[0285] R^(e) is (1) halogen,

[0286] (2) alkyl,

[0287] (3) perfluoroalkyl,

[0288] (4) —S(O)_(m)R^(i),

[0289] (5) cyano,

[0290] (6) amino,

[0291] (7) R^(i)I(CH₂)_(v)—,

[0292] (8) R^(i)CO₂(CH₂)_(v)—,

[0293] (9) R^(i)OCO(CH₂)_(v)—,

[0294] (10) optionally substituted aryl where the substituents are from1 to 3 of halogen, alkyl, alkoxy, or hydroxy, or

[0295] (11) SO₂NR^(g)R^(h);

[0296] R^(f) is (1) methyl,

[0297] (2) X—C1-C₂ alkyl, where X is O or S(O)_(m),

[0298] (3) halogen,

[0299] (4) acetylamino,

[0300] (5) trifluoromethyl,

[0301] (6) NY¹Y², where Y¹ and Y² are independently H or methyl, and

[0302] (7) hydroxy;

[0303] R^(g) and R^(h) are independently

[0304] (1) hydrogen,

[0305] (2) alkyl optionally substituted with hydroxy, amino, or CO₂R^(i)

[0306] (3) aryl optionally substituted with halogen, 1,2-methylenedioxy,alkoxy, alkyl or perfluoroalkyl,

[0307] (4) arylalkyl, wherein the aryl is optionally substituted withperfluorolkyl or 1,2-methylenedioxy;

[0308] (5) alkoxycarbonyl,

[0309] (6) alkanoyl,

[0310] (7) alkanoyl alkyl,

[0311] (9) arylalkoxycarbonyl,

[0312] (10) aminocarbonyl,

[0313] (11) monoalkylaminocarbonyl

[0314] (12) dialkylaminocarbonyl; or

[0315] R^(g) and R^(h) together with the N to which they are attachedform a 5- to 6-member ring containing 0 to 2 additional heteroatomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(e) and oxo;

[0316] R^(i) is (1) hydrogen,

[0317] (2) perfluoroalkyl,

[0318] (3) alkyl,

[0319] (4) optionally substituted arylalkyl, where the aryl substituentsare from 1 to 3 groups independently selected from halogen, alkyl,alkoxy, and hydroxy; all other variables are as defined under Formula I.

[0320] In another preferred embodiment, the present invention providescompounds of Formula I wherein

[0321] R_(i) is (1) hydrogen,

[0322] (2) optionally substituted alkyl,

[0323] (3) optionally substituted alkenyl,

[0324] (4) optionally substituted alkynyl,

[0325] where the substituents on the alkyl, alkenyl, and alkynyl are 1to 3 groups independently selected from

[0326] (i) methyl,

[0327] (ii) X-methyl, where X is O or S(O)_(m) and

[0328] (iii) halogen,

[0329] (5) aryl or arylalkyl wherein said aryl is optionally substitutedwith 1 to 3 groups independently selected from R^(f).

[0330] (6) trifluoromethyl

[0331] R₈ is (1) H,

[0332] (2) OH, or

[0333] (3) NH₂

[0334] R₉ is (1) H, or

[0335] (2) OH;

[0336] R₁₀ is (1) C(O)OR^(b),

[0337] (2) C(O)N(OR^(b))R^(c),

[0338] (3) C(O)NR^(c)R^(d),

[0339] (4) NHC(O)OR^(b),

[0340] (5) NHC(O)NR^(c)R^(d),

[0341] (6) CH₂OR^(a),

[0342] (7) CH₂OCO₂R^(b),

[0343] (8) CH₂OC(O)NR^(c)R^(d),

[0344] (9) C(O)NR^(c)NR^(c)R^(d) or

[0345] (10) C(O)NR^(c)SO₂R^(b);

[0346] R^(a) is (1) hydrogen,

[0347] (2) optionally substituted alkyl,

[0348] (3) optionally substituted alkenyl,

[0349] (4) optionally substituted alkynyl,

[0350] (5) optionally substituted alkanoyl,

[0351] (6) optionally substituted aroyl,

[0352] (7) optionally substituted cycloalkanoyl,

[0353] (8) optionally substituted cycloalkenoyl,

[0354] (9) optionally substituted alkylsulfonyl

[0355] where the substituents on the alkyl, alkenyl, alkynyl, alkanoyl,aroyl, cycloalkanoyl, cycloalkenoyl, and alkylsulfonyl, are from 1 to 5groups independently selected from hydroxy, alkoxy, aryl alkoxy,NR^(g)R^(h), CO₂R^(b), CONR^(c)R^(d) and halogen,

[0356] (10) trifluoromethyl,

[0357] (11) arylsulfonyl optionally substituted with 1 to 3 groupsindependently selected from methyl, trifluoromethyl and halogen,

[0358] (12) a 5- or 6-member heterocycle containing 1 to 4 heteroatomsselected from oxygen, sulfur and nitrogen optionally substituted by 1 to4 groups independently selected from methyl, trifluoromethyl,C(O)NR^(c)R^(d), CO₂R^(b) and halogen, and which may be saturated orpartly unsaturated;

[0359] R_(b) is (1) H,

[0360] (2) optionally substituted aryl,

[0361] (3) optionally substituted alkyl,

[0362] (4) optionally substituted alkenyl,

[0363] (5) optionally substituted alkynyl,

[0364] (6) optionally substituted cycloalkyl,

[0365] (7) optionally substituted cycloalkenyl, or

[0366] (8) optionally substituted 5- to 6-member

[0367] heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen; where the substituents on thearyl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, or alkynylare from 1 to 10 groups independently selected from

[0368] (i) hydroxy,

[0369] (ii) alkyl,

[0370] (iii) oxo,

[0371] (iv) SO₂NR^(g)R^(h),

[0372] (v) arylalkoxy,

[0373] (vi) hydroxyalkyl,

[0374] (vii) alkoxy,

[0375] (viii) hydroxy alkoxy,

[0376] (ix) amino alkoxy,

[0377] (x) cyano,

[0378] (xi) alkyl-S(O)_(m),

[0379] (xii) cycloalkyl optionally substituted with 1 to 4 groupsindependently selected from R^(e),

[0380] (xiii) cycloalkenyl,

[0381] (xiv) halogen,

[0382] (xv) alkanoyloxy,

[0383] (xvi) C(O)NR^(g)R^(h),

[0384] (xvii) CO₂R^(i),

[0385] (xvii) —NR^(g)R^(h),

[0386] (xix) 5 to 6-member heterocycle, which may be saturated orpartially unsaturated, containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen, and optionally substitutedwith 1 to 5 groups independently selected from R^(e),

[0387] (xx) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e),

[0388] (xxi) optionally substituted aryl alkoxy, wherein the arylsubstituents are 1,2-methylenedioxy or 1 to 5 groups independentlyselected from R^(e), and

[0389] (xxii) perfluoroalkyl;

[0390] R^(e) is (1) halogen,

[0391] (2) alkyl,

[0392] (3) perfluoroalkyl,

[0393] (4) —S(O)_(m)R^(i),

[0394] (5) cyano,

[0395] (6) R^(i)O(CH₂)_(v)—,

[0396] (7) R^(i)CO₂(CH₂)_(v)—,

[0397] (8) R₁₀CO(CH₂)_(v)—,

[0398] (9) optionally substituted aryl where the substituents are from 1to 3 of halogen, alkyl, alkoxy, or hydroxy,

[0399] (10) SO₂NR^(g)R^(h), or

[0400] (11) amino;

[0401] R^(f) is (1) methyl,

[0402] (2) X—C₁-C₂ alkyl, where X is O or S(O)_(m),

[0403] (3) trifluoromethyl,

[0404] (4) NY¹Y², where Y¹ and Y² are independently H or methyl,

[0405] (5) hydroxy,

[0406] (6) halogen, and

[0407] (7) acetylamino,

[0408] R^(g) and R^(h) are independently

[0409] (1) hydrogen,

[0410] (2) alkyl optionally substituted with hydroxy, amino, or CO₂R

[0411] (3) aryl optionally substituted with halogen, 1,2-methylenedioxy,alkoxy, alkyl or perfluoroalkyl,

[0412] (4) arylalkyl, wherein the aryl is optionally substituted withperfluorolkyl or 1,2-methylenedioxy;

[0413] (5) alkoxycarbonyl,

[0414] (6) alkanoyl,

[0415] (7) alkanoylalkyl,

[0416] (9) arylalkoxycarbonyl,

[0417] (10) aminocarbonyl,

[0418] (11) monoalkylaminocarbonyl

[0419] (12) dialkylaminocarbonyl; or

[0420] R^(g) and R^(h) together with the N to which they are attachedform a 5- to 6-membered ring containing 0 to 2 additional heteroatomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(e) and oxo;

[0421] R^(i) is (1) hydrogen,

[0422] (2) perfluoroalkyl,

[0423] (3) alkyl,

[0424] (4) optionally substituted aryl or arylalkyl, where the arylsubstituents are from 1 to 3 groups independently selected from halogen,alkyl, alkoxy, and hydroxy; and all other variables are as defined underFormula I. In another aspect of the present invention there are providedcompounds having the formula

[0425] where R₁-R₆, R₈ and R₉ are as defined under Formula I; and

[0426] R₁₁ is (1) COCl,

[0427] (2) CON₃, or

[0428] (3) NCO.

[0429] Most especially preferred are spot-on compositions, wherein thecomposition comprises nodulisporic acid derivatives which arenodulisporamides, which are compounds of the formula

[0430] R₁ is

[0431] (1) hydrogen,

[0432] (2) optionally substituted C₁-C₁₀ alkyl,

[0433] (3) optionally substituted C₂-C₁₀ alkenyl,

[0434] (4) optionally substituted C₂-C₁₀alkynyl,

[0435] (5) optionally substituted C₃-C₈ cycloalkyl,

[0436] (6) optionally substituted C₅-C₈ cycloalkenyl

[0437] where the substituents on the alkyl, alkenyl, alkynyl, cycloalkyland cycloalkenyl are 1 to 3 groups independently selected from C₁-C₅alkyl, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthio, C₁-C₁₀ alkylsulfonyl, C₃-C₈cycloalkyl, hydroxy, halogen, cyano, carboxy, amino, C₁-C₁₀monoalkylamino, C₁-C₁₀ dialkylamino, C₁-C₁₀ alkanoyl amino and benzoylamino wherein said benzoyl is optionally substituted with 1 to 3 groupsindependently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, C₁-C₄ alkylthio,C₂-C₄ alkenyl, C₂-C₄ alkynyl, C₁-C₃ perfluoroalkyl, amino, hydroxy,halogen, C₁-C₅ monoalkylamino, C₁-C₅ dialkylamino and C₁-C₅ alkanoylamino,

[0438] (7) phenyl C₀₋C₅ alkyl wherein said phenyl is optionallysubstituted with 1 to 3 groups independently selected from C₁-C₄ alkyl,C₁-C₄ alkoxy, C₁-C₄ alkylthio, C₂-C₄ alkenyl, C₂-C₄ alkynyl, C_(1-C) ₃perfluoroalkyl, amino, hydroxy, carboxy, halogen, C₁-C₅ monoalkylamino,C₁-C₅ dialkylamino and C₁-C₅ alkanoyl amino,

[0439] (8) C₁-C₅ perfluoroalkyl,

[0440] (9) a 5- or 6-member ring selected from morpholino, pyridyl andpiperazino, optionally substituted by 1 to 3 groups independentlyselected from hydroxy, oxo, C₁-C₁₀ alkyl and halogen,

[0441] R², R³, and R⁴ are independently OR^(a), OCO₂R^(b),OC(O)NR^(c)R^(d); or

[0442] R¹ and R² together represent ═O, ═NOR^(a) or ═N—NR^(c)R^(d);

[0443] R⁵ is NR^(c)R^(d),

[0444] R ^(a) is

[0445] (1) hydrogen,

[0446] (2) optionally substituted C₁-C₁₀ alkyl,

[0447] (3) optionally substituted C₃-C₁₀ alkenyl,

[0448] (4) optionally substituted C₃-C₁₀ alkynyl,

[0449] (5) optionally substituted C₁-C₁₀ alkanoyl,

[0450] (6) optionally substituted C₁-C₁₀ alkenoyl,

[0451] (7) optionally substituted C₁-C₁₀ alkynoyl,

[0452] (8) optionally substituted benzoyl,

[0453] (9) optionally substituted phenyl,

[0454] (10) optionally substituted C₁-C₇ cycloalkanoyl,

[0455] (11) optionally substituted C₄-C₇ cycloalkenoyl,

[0456] (12) optionally substituted C₁-C₁₀ alkylsulfonyl

[0457] (13) optionally substituted C₃-C₈ cycloalkyl

[0458] (14) optionally substituted C₅-C₈ cycloalkenyl

[0459] where the substituents on the alkyl, alkenyl, alkynyl, alkanoyl,alkenoyl, alkynoyl, benzoyl, phenyl, cycloalkanoyl, cycloalkenoyl,alkylsulfonyl, cycloalkyl and cycloalkenyl are from 1 to 5 groupsindependently selected from hydroxy, C₁-C₆ alkoxy, C₃-C₇ cycloalkyl,aryl C₁-C₃ alkoxy, NR^(g)R^(h), CO₂R^(b), CONR^(c)R^(d) and halogen,

[0460] (15) C₁-C₅ perfluoroalkyl,

[0461] (16) phenylsulfonyl optionally substituted with 1 to 3 groupsindependently selected from C₁-C₅ alkyl, C₁₋C₅ perfluoroalkyl, nitro,halogen or cyano,

[0462] (17) a 5- or 6-member ring selected from piperidino, morpholino,pyridyl and piperazino optionally substituted by 1 to 4 groupsindependently selected from C₁-C₅ alkyl, C₁-C₅ alkenyl, C₁-C₅perfluoroalkyl, amino, C(O)R^(c)R^(d), cyano, CO₂R^(b) or halogen;

[0463] R^(b) is

[0464] (1) H,

[0465] (2) optionally substituted phenyl,

[0466] (3) optionally substituted C₁-C₁₀ alkyl,

[0467] (4) optionally substituted C₃-C₁₀ alkenyl, or

[0468] (5) optionally substituted C₃-C₁₀ alkynyl,

[0469] where the substituents on the phenyl, alkyl, alkenyl or alkynylare from 1 to 5 groups independently selected from hydroxy, C₁-C₆alkoxy, C₃-C₇ cycloalkyl, halogen, C₁-C₅ alkanoyloxy, C(O)NR^(c)R^(d),CO₂R^(b), formyl, —NR^(g)R^(h), optionally substituted phenyl, andoptionally substituted phenyl C₁-C₃ alkoxy, wherein the phenylsubstituents are 1 to 3 groups independently selected from R^(e);

[0470] R^(c) and R^(d) are independently R^(b); or

[0471] R^(c) and R^(d) together with the N to which they are attachedform a piperidino, morpholino or piperazino optionally substituted with1 to 3 groups independently selected from R^(g) and oxo;

[0472] R^(e) is

[0473] (1) halogen,

[0474] (2) C₁-C₇ alkyl,

[0475] (3) C₁-C₃ perfluoroalkyl,

[0476] (4) —S(O)_(m)R^(i),

[0477] (5) cyano,

[0478] (6) nitro,

[0479] (7) R^(j)O(CH₂)_(v)—,

[0480] (8) R^(j)CO₂ (CH₂)_(v)—,

[0481] (9) R^(j)OCO(CH₂)_(v) ⁻,

[0482] (10) optionally substituted phenyl where the substituents arefrom 1 to 3 halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, or hydroxy;

[0483] v is 0 to 3;

[0484] R^(g) and R^(h) are independently

[0485] (1) hydrogen,

[0486] (2) C₁-C₆ alkyl,

[0487] (3) aryl,

[0488] (4) aryl C₁-C₆ alkyl,

[0489] (5) C₁-C₅ alkoxycarbonyl,

[0490] (6) C₁-C₅ alkylcarbonyl, or

[0491] (7) C₁-C₅ alkanoyl C₁-C₅ alkyl; or

[0492] R^(g) and R^(h) together with the N to which they are attachedform a piperidino, morpholino or piperazino optionally substituted with1 to 3 groups independently selected from R^(g) and oxo;

[0493] R^(i) and R^(j) are independently

[0494] (1) hydrogen,

[0495] (2) C₁-C₃ perfluoroalkyl,

[0496] (3) optionally substituted C₁-C₆ alkyl, where the substituentsare aryl or substituted phenyl;

[0497] (4) phenyl or substituted phenyl where the substituents are from1 to 3 groups independently selected from halogen, C₁-C₆ alkyl, C₁-C₆alkoxy, or hydroxy;

[0498] m is 0 to 2; or a pharmaceutically acceptable salt thereof.

[0499] Most especially preferred are compounds of the formula

[0500] wherein R^(x) is selected from the group consisting of:

[0501] H, CH₃, CH₂CH₃, C(CH₃)₃, CH₂CH₂CH₃, CH₂CH₂OH, CH(CO₂CH₃)CH₂OH,CH₂CO₂CH₃, CH₂CH(OCH₂CH₃)₂, CH₂CH₂OCH₂CH₂OH, CH(CH₃)(CH₂)₃C(CH₃)₂OH,(CH₂)₃OH, (CH₂)₄OH, (CH₂)SOH, CH(CH₂OH)CH₂CH₃, NHC(CH₃)₃, CH₂CN,(CH₂)₆OH, CH₂CH(OH)CH₃, CH(CH₂OH)CH₂CH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃,CH₂CONH, CH(CH₃)(CH₂OH)₂, CH₂CH₂NHCH₂CH₂OH, CH(CH₂OH)(CH₂)₃CH₃,CH(CH₂OCH₃)CH₃, (CH₂)₂SH, (CH₂)₄NH₂, CH₂CH₂SO₂CH₃, CH₂CH₂S(O)CH₃,CH(CH(CH₃)₂)CH₂OH, (CH₂)₃NH₂, (CH₂)₃N(CH₂CH₃)₂, (CH₂)₃N(CH₃)₂, OCH₂CH₃,CH₂CH(OH)CH₂OH, OCH₃, CH₂CH₂OCH₃, CH₂CH₂NHC(O)CH₃, C(CH₃)₂CH₂OH, c-C₃H₅,c-C₆H₁₁, (CH₂)₃OCH₂CH₃, CH₂CH≡CH₂, C(CH₂CH₃)(CH₂OH)₂, CH₂C≡CH,CH₂CO₂CH₂CH₃, CH₂CH₂F, (CH₂)₃OCH₂)₁₁ CH₃, CH₂CH₂N(CH₃)₂,CH₂CH₂OCH₂CH₂NH₂, CH₂CF₃, NHCH₂CO₂CH₂CH₃, CH(CH₃)CO₂CH₃,C(CH₃)₂CH₂C(O)CH₃, CH(CO₂CH₂CH₃)₂, CH₂CH₃, CH(CH₂CH₂CH₃)CO₂CH₃,CH₂CH₂CH₂OCH₃, C(CH₃)₂C≡CH, (CH₂)₄CH₃, CH(CH₂CH₂CH₃)₂, (CH₂)₅CH₃,CH₂CH₂CO₂H, CH(CH(CH₃)₂)CO₂CH₃, OCH₂CO₂H, CH(CH(CH₃)₂)CH₂OH,CH(CH(CH₃)₂)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)₂, C(CH₃)₃,(CH₂)CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)OH, (CH₂)₃CH₃, (CH₂)₂OCH₂CH₃,1-adamantyl, (CH₂)₈CH₃, CH(CH₃)CH(CH₃)₂, (CH₂)₃NHCH₃, (CH₂)₂N(CH₂CH₃)₂,

[0502] An especially preferred nodulisporamide derivative is one whereinR^(x) is with t-butyl being most especially preferred.

[0503] “Alkyl” as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, alkenyl, alkynyl and the like, means carbon chainswhich may be linear or branched or combinations thereof. Examples ofalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- andtert-butyl, pentyl, hexyl, heptyl and the like. “Alkenyl”, “alkynyl” andother like terms include carbon chains containing at least oneunsaturated C—C bond.

[0504] The term “cycloalkyl” means carbocycles containing noheteroatoms, and includes mono-, bi- and tricyclic saturatedcarbocycles, as well as benzofused carbocycles. Examples of cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,decahydronaphthalene, adamantane, indanyl, indenyl, fluorenyl,1,2,3,4-tetrahydronaphalene and the like. Similarly, “cycloalkenyl”means carbocycles containing no heteroatoms and at least onenon-aromatic C—C double bond, and include mono-, bi- and tricyclicpartially saturated carbocycles, as well as benzofused cycloalkenes.Examples of cycloalkenyl include cyclohexenyl, indenyl, and the like.

[0505] The term “halogen” is intended to include the halogen atomsfluorine, chlorine, bromine and iodine.

[0506] The term “heterocycle”, unless otherwise specfied, means mono- orbicyclic compounds that are saturated or partly unsaturated, as well asbenzo- or heteroaromatic ring fused saturated heterocycles or partlyunsaturated heterocycles, and containing from 1 to 4 heteroatornsindependently selected from oxygen, sulfur and nitrogen. Examples ofsaturated heterocycles include morpholine, thiomorpholine, piperidine,piperazine, tetrahydropyran, tetrahydrofuran, dioxane,tetrahydrothiophene, oxazolidine, pyrrolidine; examples of partlyunsaturated heterocycles include dihydropyran, dihydropyridazine,dihydrofuran, dihydrooxazole, dihydropyrazole, dihydropyridine,dihydropyridazine and the like. Examples of benzo- or heteroaromaticring fused heterocycle include 2,3-dihydrobenzofuranyl, benzopyranyl,tetrahydroquinoline, tetrahydroisoquinoline, benzomorpholinyl,1,4-benzodioxanyl, 2,3-dihydrofuro(2,3-b)pyridyl and the like.

[0507] The term “aryl” is intended to include mono- and bicyclicaromatic and heteroaromatic rings containing from 0 to 5 heteroatomsindependently selected from nitrogen, oxygen and sulfur. The term “aryl”is also meant to include benzofused cycloalkyl, benzofused cycloalkenyl,and benzofused heterocyclic groups. Examples of “aryl” groups includephenyl, pyrrolyl, isoxazolyl, pyrazinyl, pyridinyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl,pyrimidinyl, pyridazinyl, pyrazinyl, naphthyl, benzoxazolyl,benzothiazolyl, benzimidazolyl, benzofuranyl, furo(2,3-B)pyridyl,2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, benzothiophenyl,quinolinyl, indolyl, 2,3-dihydrobenzofuranyl, benzopyranyl,1,4-benzodioxanyl, indanyl, indenyl, fluorenyl,1,2,3,4-tetrahydronaphthalene and the like.

[0508] Aroyl means arylcarbonyl in which aryl is as defined above.

[0509] Examples of NR^(c)R^(d) or NR^(g)R^(h) forming a 3- to10-membered ring containing 0 to 2 additional heteroatoms selected fromO, S(O)_(m) and N are aziridine, azetidine, pyrrolidine, piperidine,thiomorpholine, morpholine, piperazine, octahydroindole,tetrahydroisoquinoline and the like.

[0510] The term “optionally substituted” is intended to include bothsubstituted and unsubstituted; thus, for example, optionally substitutedaryl could represent a pentafluorophenyl or a phenyl ring.

[0511] Certain of the above defined terms may occur more than once inthe above formula and upon such occurrence each term shall be definedindependently of the other; thus, for example, OR^(a) at C4 mayrepresent OH

[0512] Compounds of formula (I) are available commercially or can beprepared according to one or other of the processes or any other processcoming within the competence of a person skilled in the art who is anexpert in chemical synthesis. For the chemical preparation of theproducts of the invention, a person skilled in the art is regarded ashaving at his disposal, inter alia, the entire contents of “ChemicalAbstracts” and of the documents which are cited therein. Semi-syntheticprocesses are described, for example, in U.S. Pat. No. 6,399,786 or WO96/29073, both of which are incorporated by reference.

[0513] A particularly effective synthetic method in order to preparenodulisporamide compounds of the formula

[0514] wherein R₁, R₂, R₃ and R₄ are defined above and R⁵¹ isNR^(c)R^(d) where R^(c)R^(d) are independently

[0515] (1) H,

[0516] (2) optionally substituted aryl,

[0517] (3) optionally substituted alkyl,

[0518] (4) optionally substituted alkenyl,

[0519] (5) optionally substituted alkynyl,

[0520] (6) optionally substituted cycloalkyl,

[0521] (7) optionally substituted cycloalkenyl, or

[0522] (8) optionally substituted heterocycle containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen;where the substituents on the aryl, alkyl, alkenyl, cycloalkyl,cycloalkenyl, heterocycle, or alkynyl are from 1 to 10 groupsindependently selected from

[0523] (i) hydroxy,

[0524] (ii) alkyl,

[0525] (iii) oxo,

[0526] (iv) SO₂NR^(g)R^(h),

[0527] (v) arylalkoxy,

[0528] (vi) hydroxyalkyl,

[0529] (vii) alkoxy,

[0530] (viii) hydroxyalkoxy,

[0531] (ix) aminoalkoxy,

[0532] (x) cyano,

[0533] (xi) mercapto,

[0534] (xii) alkyl-S(O)_(m),

[0535] (xiii) cycloalkyl optionally substituted

[0536] with 1 to 4 groups independently selected from R^(e),

[0537] (xiv) cycloalkenyl,

[0538] (xv) halogen,

[0539] (xvi) alkanoyloxy,

[0540] (xvii) C(O)NR^(g)R^(h),

[0541] (xviii) CO₂R^(i),

[0542] (xix) formyl,

[0543] (xx) —NR^(g)R^(h),

[0544] (xxi) 5 to 9-member heterocycle, which may be saturated orpartially unsaturated, containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen, and optionally substitutedwith 1 to 5 groups independently selected from R^(e),

[0545] (xxii) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e),

[0546] (xxiii) optionally substituted arylalkoxy,

[0547] wherein the aryl substituents are 1,2-methylenedioxy or 1 to 5groups independently selected from R^(e),

[0548] (xxiv) perfluoroalkyl; or

[0549] R^(c) and R^(d) together with the N to which they are attachedform a 3- to 10-member ring containing 0 to 2 additional heteroatomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(g), hydroxy, thioxo and oxo;

[0550] R^(e) is (1) halogen,

[0551] (2) alkyl,

[0552] (3) perfluoroalkyl,

[0553] (4) —S(O)_(m)R^(i),

[0554] (5) cyano,

[0555] (6) nitro,

[0556] (7) R^(i)O(CH₂)_(v)—,

[0557] (8) R^(i)CO₂(CH₂)_(v)—,

[0558] (9) R_(i)OCO(CH₂)_(v)—,

[0559] (10) optionally substituted aryl where the substituents are from1 to 3 of halogen, alkyl, alkoxy, or hydroxy,

[0560] (11) SO₂NR^(g)R^(h), or

[0561] (12) amino;

[0562] R^(f) is (1) alkyl,

[0563] (2) X-alkyl, where X is O or S(O)_(m),

[0564] (3) alkenyl,

[0565] (4) alkynyl,

[0566] (5) perfluoroalkyl,

[0567] (6) NY¹Y², where Y¹ and Y² are independently H or alkyl,

[0568] (7) hydroxy,

[0569] (8) halogen, and

[0570] (9) alkanoyl amino,

[0571] R^(g) and R^(h) are independently

[0572] (1) hydrogen,

[0573] (2) alkyl optionally substituted with hydroxy, amino, or CO₂R^(i)

[0574] (3) aryl optionally substituted with halogen, 1,2-methylenedioxy,alkoxy, alkyl or perfluoroalkyl,

[0575] (4) arylalkyl, wherein the aryl is optionally substituted withperfluorolkyl or 1,2-methylenedioxy;

[0576] (5) alkoxycarbonyl,

[0577] (6) alkanoyl,

[0578] (7) alkanoylalkyl,

[0579] (9) arylalkoxycarbonyl,

[0580] (10) aminocarbonyl,

[0581] (11) monoalkylaminocarbonyl

[0582] (12) dialkylaminocarbonyl; or

[0583] R^(g) and R^(h) together with the N to which they are attachedform a 3- to 7-member ring containing 0 to 2 additional heteroatomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(e) and oxo;

[0584] R^(i) is (1) hydrogen,

[0585] (2) perfluoroalkyl,

[0586] (3) alkyl,

[0587] (4) optionally substituted aryl, or arylalkyl, where the arylsubstituents are from 1 to 3 groups independently selected from halogen,alkyl, alkoxy, and hydroxy;

[0588] m is 0 to 2; and

[0589] v is 0 to 3; or

[0590] said process comprising

[0591] (1) coupling a compound of formula II′

[0592] wherein

[0593] R¹, R², R³, and R⁴ are defined above,

[0594] with a compound of formula III

[0595] wherein R^(6′) and R^(7′) can be independently selected fromalkyl, aminoalkyl or cycloalkyl, in the presence of an organic solventto produce a first intermediate compound of the formula:

[0596] (2) reacting the first intermediate compound with an activatingcompound ACT, such as a compound of formula IV

[0597] to produce a second intermediate compound of the formula:

[0598] (3) adding an amine of the formula HNR^(c)R^(d) to the secondintermediate compound to obtain a compound of formula I′.

[0599] This process is described in Provisional Application No.60/415,627, entitled “Method for the Synthesis of Nodulisporamide,”filed on Oct. 2, 2002, herein incorporated by reference.

[0600] The advantage to the invention process is that the amidationreaction occurs under mild conditions, thereby reducing the potential ofside reactions at the C₂₃-C₂₄ position or epimerization of C₇ of thestarting material. This in turn increases the overall yield and purityof the final product. It is known that amidation under acidic conditionsleads to dehydration of the C₂₃-C₂₄ position and amidation under basicconditions leads to epimerization of C₇; the inventive process is mildenough to reduce greatly the occurrence of these side reactions.

[0601] The inventive process achieves these results by performing theamidation reaction via an active intermediate by reacting thenodulisporic acid compound with a compound of formula III. Preferredcompounds of formula III are N-N′-Diisopropylcarbodiimide (DIPCDI)N-N′-dicyclohexylcarbodimide (DCC), and1-[(3-dimethylamino)propyl]-3-ethylcarbodimide HCl salt (EDC) with DCCbeing especially preferred. This intermediate may be isolated or it maybe reacted in one step with an activating compound such as a1-hydroxybenzotriazole (HOBT) [Formula IV]. Other compounds which can beused as activating compounds include 2-hydroxypyridine-N-oxide (HOPO),2-hydroxypyridine and 1-hydroxysuccinimide.

[0602] The amines of the formula HNR^(c)R^(d) are well known to apractioner of this art and are obtainable either commercially or bymodification of known synthetic techniques, such as those found in“Organic Synthesis”, a source that is well-known and used by apractitioner in the field. Preferred aminos include, for example, amineswherein R^(c) is H and R^(d) is selected from the group consisting of:

[0603] H, CH₃, CH₂CH₃, C(CH₃)₃, CH₂CH₂CH₃, CH₂CH₂OH, CH(CO₂CH₃)CH₂OH,CH₂CO₂CH₃, CH₂CH(OCH₂CH₃)₂, CH₂CH₂OCH₂CH₂OH, CH(CH₃)(CH₂)₃C(CH₃)₂OH,(CH₂)₃OH, (CH₂)₄OH, (CH₂)SOH, CH(CH₂OH)CH₂CH₃, NHC(CH₃)₃, CH₂CN,(CH₂)₆OH, CH₂CH(OH)CH₃, CH(CH₂OH)CH₂CH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃,CH₂CONH₂, CH(CH₃)(CH₂OH)₂, CH₂CH₂NHCH₂CH₂OH, CH(CH₂OH)(CH₂)₃CH₃,CH(CH₂OCH₃)CH₃, (CH₂)₂SH, (CH₂)₄NH₂, CH₂CH₂SO₂CH₃, CH₂CH₂S(O)CH₃,CH(CH(CH₃)₂)CH₂OH, (CH₂)₃NH₂, (CH₂)₃N(CH₂CH₃)₂, (CH₂)₃N(CH₃)₂, OCH₂CH₃,CH₂CH(OH)CH₂OH, OCH₃, CH₂CH₂OCH₃, CH₂CH₂NHC(O)CH₃, C(CH₃)₂CH₂OH, c-C₃H₅,cC₆H₁₁, (CH₂)₃OCH₂CH₃, CH₂CH═CH₂, C(CH₂CH₃)(CH₂OH)₂, CH₂C≡CH,CH₂CO₂CH₂CH₃, CH₂CH₂F, (CH₂)₃O(CH₂)₁₁CH₃, CH₂CH₂N(CH₃)₂,CH₂CH₂OCH₂CH₂NH₂, CH₂CF₃, NHCH₂CO₂CH₂CH₃, CH(CH₃)CO₂CH₃,C(CH₃)₂CH₂C(O)CH₃, CH(CO₂CH₂CH₃)₂, CH₂CH₃, CH(CH₂CH₂CH₃)CO₂CH₃,CH₂CH₂CH₂OCH₃, C(CH₃)₂CH₂C≡CH, (CH₂)₄CH₃, CH(CH₂CH₂CH₃)₂, (CH₂)SCH₃,CH₂CH₂CO₂H, CH(CH(CH₃)₂)CO₂CH₃, OCH₂CO₂H, CH(CH(CH₃)₂)CH₂OH,CH(CH(CH₃)₂)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)₂, C(CH₃)₃,(CH₂)CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)OH, (CH₂)₃CH₃, (CH₂)₂OCH₂CH₃,1-adamantyl, (CH₂)₈CH₃, CH(CH₃)CH(CH₃)₂, (CH₂)₃NHCH₃, (CH₂)₂N(CH₂CH₃)₂,

[0604] Preferred solvents for this reaction include halogenatedhydrocarbons, such as dichloromethane and ethylene chloride, ethers,such as methyl t-butyl ether (MTBE), diethyl ether or tetraydrofuran(THF), or mixtures of the foregoing. Other solvents include polaraprotic solvents including but not limited to dimethoxymethane,2-methyltetrahydrofuran, methyl iso-butylketone, benzotrifuoride andmethylacetate. Perferably, the inventive process uses a homogeneoussolvent system that dissolves both the nodulisporic acid derivatives andthe activation agents and avoids the prior process, which perform theactivating/coupling reaction two phase water-organic solvent system,thereby permitting the reaction to run faster and obtain conversion moreeasily. A mixture of MTBE and THF is especially preferred. Preferredranges of MTBE to THF are about 5:1 to about 1:2, with about 4:1 toabout 2:3 being especially preferred.

[0605] The amount of DCC and HOBT should be in molar excess to achievefull conversion. A preferred range would be from about 1.1 to about 2.5,with about 1.2 to about 1.8 equivalents being especially preferred.

[0606] Reaction temperatures range from about 10° C. to about 50° C.with about 20° C. to about 30° C. being especially preferred.

[0607] Optionally, the nodulisporamide derivative may be recrystallizedto obtain a product with better purity. Suitable recrystallizationsolvents include a mixture of a polar solvent such as water,acetonitrile, acetone and an apolar solvent such as alkanes andcycloalkanes including but not limited to pentane, hexane,cyclohepatane, cyclohexane, cyclohepatane. Preferred mixture ofrecrystallization solvent include acetone/heptane with few drops ofwater. An especially preferred mixture of solvents include firstoptionally recrystallizing from acetonitrile/water followed byacetone/heptane.

[0608] Compounds of formula V′ are also novel and are part of thisinvention.

[0609] Administration of the inventive formulation may be intermittentin time and may be administered daily, weekly, biweekly, monthly,bimonthly, quarterly, or even for longer durations of time. The timeperiod between treatments depends upon factors such as the parasite(s)being treated, the degree of infestation, the type of mammal or bird andthe environment where it resides. It is well within the skill level ofthe practitioner to determine a specific administration period for aparticular situation. This invention contemplates a method forpermanently combating a parasite in an environment in which the animalis subjected to strong parasitic pressure where the administration is ata frequency far below a daily administration in this case. For example,it is preferable for the treatment according to the invention to becarried out monthly on dogs and on cats.

[0610] Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation can be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host. The compounds may be administeredcontinuously, particularly for prophylaxis, by known methods.

[0611] Generally, a dose of from about 0.001 to about 100 mg per kg ofbody weight, with a range of 0.25 to 50 mg/kg being especiallypreferred, given as a single dose or in divided doses for a period offrom about 1 to about 60 days, preferably from about 1 to 30 days, willbe satisfactory but, of course, there can be instance where higher orlower dosage ranges are indicated and such are within the scope of thisinvention. It is well within the routine skill of the practitioner todetermine a particular dosing regimen for a specific host and parasite.

[0612] It also may be preferable to use controlled-release formulations.

[0613] The invention also relates to such a method with a therapeuticaim intended for the treatment and prevention of parasitoses havingpathogenic consequences.

[0614] This invention also provides for formulations wherein thenodulisporic acid or derivative thereof is combined with a second activeagent, such a parasiticide. Examples of classes of these compoundsinclude avermectins, milbemycins, 1-N-arylpyrazoles, IGR compounds,etc., some of which are discussed above.

[0615] The formulations of the present invention provide for the topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders. It has been discovered that the inventiveformulations are especially active against parasites when theformulations are applied to mammals and birds, especially poultry, dogs,cats, sheep, pigs, cattle and horses. These formulations comprise acomposition of an effective amount of at least one nodulisporic acidderivative dissolved in a pharmaceutical or veterinary acceptablecarrier vehicle where a crystallization inhibitor is optionally present.The nodulisporic acid derivative are advantageously resent in theinventive formulation in a proportion of about 1 to about 40%,preferably of about 1 to about 30% and most preferably about 5 to about15% (percentages as weight by volume=W/V). The liquid carrier vehiclecomprises a pharmaceutically or veterinary acceptable organic solventand optionally an organic cosolvent.

[0616] Also contemplated are the pharmaceutically or veterinaryacceptable acid or base salts, where applicable, of the active compoundsprovided for herein. The term “acid” contemplates all pharmaceuticallyor veterinary acceptable inorganic or organic acids. Inorganic acidsinclude mineral acids such as hydrohalic acids, such as hydrobromic andhydrochloric acids, sulfuric acids, phosphoric acids and nitric acids.Organic acids include all pharmaceutically or veterinary acceptablealiphatic, alicyclic and aromatic carboxylic acids, dicarboxylic acidstricarboxylic acids and fatty acids. Preferred acids are straight chainor branched, saturated or unsaturated C₁-C₂₀ aliphatic carboxylic acids,which are optionally substituted by halogen or by hydroxyl groups, orC₆-C₁₂ aromatic carboxylic acids. Examples of such acids are carbonicacid, formic acid, fumaric acid, acetic acid, propionic acid,isopropionic acid, valeric acid, α-hydroxy acids, such as glycolic acidand lactic acid, chloroacetic acid, benzoic acid, methane sulfonic acid,and salicylic acid. Examples of dicarboxylic acids include oxalic acid,malic acid, succinic acid, tartaric acid and maleic acid. An example ofa tricarboxylic acid is citric acid. Fatty acids include allpharmaceutically or veterinary acceptable saturated or unsaturatedaliphatic or aromatic carboxylic acids having 4 to 24 carbon atoms.Examples include butyric acid, isobutyric acid, sec-butyric acid, lauricacid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenicacid, and phenylsteric acid. Other acids include gluconic acid,glycoheptonic acid and lactobionic acid.

[0617] The term “base” contemplates all pharmaceutically or veterinaryacceptable inorganic or organic bases. Such bases include, for example,the alkali metal and alkaline earth metal salts, such as the lithium,sodium, potassium, magnesium or calcium salts. Organic bases include thecommon hydrocarbyl and heterocyclic amine salts, which include, forexample, the morpholine and piperidine salts.

[0618] The organic solvent for the liquid carrier vehicle willpreferably have a dielectric constant of between about 10 and about 35,preferably between about 20 and about 30, the content of this solvent inthe overall composition preferably representing the remainder to 100% ofthe composition. It is well within the skill level of the practitionerto select a suitable solvent on the basis of these parameters.

[0619] The organic cosolvent for the liquid carrier vehicle willpreferably have a boiling point of less than about 100° C., preferablyof less than about 80° C., and will have a dielectric constant ofbetween about 10 and about 40, preferably between about 20 and about 30;this cosolvent can advantageously be present in the compositionaccording to a weight/weight (W/W) ratio with respect to the solvent ofbetween about 1/15 and about 1/2; the cosolvent is volatile in order toact in particular as drying promoter and is miscible with water and/orwith the solvent. Again, it is well within the skill level of thepractitioner to select a suitable solvent on the basis of theseparameters.

[0620] The organic solvent for the liquid carrier includes the commonlyacceptable organic solvents known in the formulation art. These solventsmay be found, for example, in Remington Pharmaceutical Science, 16^(th)Edition (1986). These solvents include, for example, acetone, ethylacetate, methanol, ethanol, isopropanol, dimethylformamide,dichloromethane or diethylene glycol monoethyl ether (Transcutol). Thesesolvents can be supplemented by various excipients according to thenature of the desired phases, such as C₈-C₁₀ caprylic/caprictriglyceride (Estasan or Miglyol 812), oleic acid or propylene glycol.

[0621] The liquid carrier may also comprise a microemulsion.Microemulsions are also well suited as the liquid carrier vehicle.Microemulsions are quaternary systems comprising an aqueous phase, anoily phase, a surfactant and a cosurfactant. They are translucent andisotropic liquids.

[0622] Microemulsions are composed of stable dispersions ofmicrodroplets of the aqueous phase in the oily phase or conversely ofmicrodroplets of the oily phase in the aqueous phase. The size of thesemicrodroplets is less than 200 nm (1000 to 100,000 nm for emulsions).The interfacial film is composed of an alternation of surface-active(SA) and co-surface-active (Co-SA) molecules which, by lowering theinterfacial tension, allows the microemulsion to be formedspontaneously.

[0623] The oily phase can in particular be formed from mineral orvegetable oils, from unsaturated polyglycosylated glycerides or fromtriglycerides, or alternatively from mixtures of such compounds. Theoily phase preferably comprises triglycerides and more preferablymedium-chain triglycerides, for example C₈-C₁₀ caprylic/caprictriglyceride. The oily phase will represent, in particular, from about 2to about 15%, more particularly from about 7 to about 10%, preferablyfrom about 8 to about 9%, V/V of the microemulsion.

[0624] The aqueous phase includes, for example water or glycolderivatives, such as propylene glycol, glycol ethers, polyethyleneglycols or glycerol. Propylene glycol, diethylene glycol monoethyl etherand dipropylene glycol monoethyl ether are especially preferred.Generally, the aqueous phase will represent a proportion from about 1 toabout 4% V/V in the microemulsion.

[0625] Surfactants for the microemulsion include diethylene glycolmonoethyl ether, dipropyelene glycol monomethyl ether, polyglycolysedC₈-C₁₀ glycerides or polyglyceryl-6 dioleate. In addition to thesesurfactants, the cosurfactants include short-chain alcohols, such asethanol and propanol.

[0626] Some compounds are common to the three components discussedabove, i.e., aqueous phase, surfactant and cosurfactant. However, it iswell within the skill level of the practitioner to use differentcompounds for each component of the same formulation.

[0627] The cosurfactant to surfactant ratio will preferably be fromabout 1/7 to about 1/2. There will preferably be from about 25 to about75% V/V of surfactant and from about 10 to about 55% V/V of cosurfactantin the microemulsion.

[0628] Likewise, the co-solvents are also well known to a practitionerin the formulation art. Preferred co-solvents are those which is apromoter of drying and include, for example, absolute ethanol,isopropanol (2-propanol) or methanol.

[0629] If present, it is preferred that the crystallization inhibitor ispresent in a proportion of about 1 to about 20% (W/V), preferably ofabout 5 to about 15%. The inhibitor preferably corresponds to the testin which 0.3 ml of a solution comprising 10% (W/V) of the compound offormula (1) in the liquid carrier and 10% of the inhibitor are depositedon a glass slide at 20° C. and allowed to stand for 24 hours. The slideis then observed with the naked eye. Acceptable inhibitors are thosewhose addition provides for few or no crystals, and in particular lessthan 10 crystals, preferably 0 crystals.

[0630] Although this is not preferred, the formulation can optionallycomprise water, in particular in a proportion of 0 to about 30% (volumeby volume V/V), in particular of 0 to about 5%.

[0631] The formulation can also comprise an antioxidizing agent intendedto inhibit oxidation in air, this agent being in particular present in aproportion of about 0.005 to about 1% (W/V), preferably of about 0.01 toabout 0.05%.

[0632] Crystallization inhibitors which can be used in the inventioninclude:

[0633] polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and of vinylpyrrolidone, polyethylene glycols, benzyl alcohol,mannitol, glycerol, sorbitol or polyoxyethylenated esters of sorbitan;lecithin or sodium carboxymethylcellulose; or acrylic derivatives, suchas methacrylates and others,

[0634] anionic surfactants, such as alkaline stearates, in particularsodium, potassium or ammonium stearate; calcium stearate ortriethanolamine stearate; sodium abietate; alkyl sulphates, inparticular sodium lauryl sulphate and sodium cetyl sulphate; sodiumdodecylbenzenesulphonate or sodium dioctyl sulphosuccinate; or fattyacids, in particular those derived from coconut oil,

[0635] cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y⁻ is ananion of a strong acid, such as halide, sulphate and sulphonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used,

[0636] amine salts of formula N⁺R′R″R′″, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used,

[0637] non-ionic surfactants, such as optionally polyoxyethylenatedesters of sorbitan, in particular Polysorbate 80, or polyoxyethylenatedalkyl ethers; polyethylene glycol stearate, polyoxyethylenatedderivatives of castor oil, polyglycerol esters, polyoxyethylenated fattyalcohols, polyoxyethylenated fatty acids or copolymers of ethylene oxideand of propylene oxide,

[0638] amphoteric surfactants, such as substituted lauryl compounds ofbetaine,

[0639] or preferably a mixture of at least two of the compounds listedabove.

[0640] In a particularly preferred embodiment, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected in particular fromthe compounds mentioned above as crystallization inhibitor.

[0641] Particularly preferred film-forming agents of polymeric typeinclude:

[0642] the various grades of polyvinylpyrrolidone,

[0643] polyvinyl alcohols, and

[0644] copolymers of vinyl acetate and of vinylpyrrolidone.

[0645] Especially preferred surface-active agents, include those made ofnon-ionic surfactants, preferably polyoxyethylenated esters of sorbitanand in particular the various grades of polysorbate, for examplePolysorbate 80.

[0646] The film-forming agent and the surface-active agent can inparticular be incorporated in similar or identical amounts within thelimit of the total amounts of crystallization inhibitor mentionedelsewhere.

[0647] The pair thus constituted secures, in a noteworthy way, theobjectives of absence of crystallization on the coat and of maintenanceof the cosmetic appearance of the fur, that is to say without a tendencytowards sticking or towards a sticky appearance, despite the highconcentration of active material.

[0648] Particularly preferred antioxidizing agents are thoseconventional in the art and include, for example, butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulphate or a mixture of notmore than two of them.

[0649] The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

[0650] The volume applied can be of the order of about 0.3 to about 1ml, preferably of the order of about 0.5 ml, for cats and of the orderof about 0.3 to about 5 ml for dogs, depending on the weight of theanimal.

[0651] The formulations according to the invention are extremelyeffective for long durations of time in the treatment of parasites suchas fleas of mammals and, in particular, of small mammals such as dogsand cats. The inventive formulations exhibit a degree of effectivenessagainst other parasitic insects and in particular fleas and ticks. Theinventive formulations further exhibit synergy when treatinginfestations cause by ectoparasites and endoparasites.

[0652] Other advantages and characteristics of the invention will becomeapparent on reading the following description, given by way ofnon-limiting examples.

EXAMPLES Example 1 Topical Spot-On Formulation (20% w/v t-butylNodulisporamide)

[0653] A spot-on formulation comprising the following ingredients wasprepared by mixing the following ingredients Component Amount (% w/v)t-butyl nodulisporamide 20 Tenox 2 (antioxidant) 0.02 Transcutol(carrier) 100 qs

Example 2 Topical Spot-On Formulation (10% w/v t-butyl Nodulisporamide)

[0654] A spot-on formulation comprising t-butyl nodulisporamide wasprepared by moving the following ingredients Ingredient Amount (% w/v)t-butyl nodulisporamide 10 Tenox 2 (antioxidant) 0.02 Miglyol 840(additive) 10 Povidone (crystallization inhibitor) 5 Transcotol (liquidcarrier) 100 qs

Example 3 Long Term Efficacy

[0655] The spot-on formulation according to Example 1 was applied tofour dogs infested with fleas for a thirty-five day period. The resultsare summarized below Day 1 7 14 21 28 35 % effic 100 99.7 100 99.6 89.371.8

[0656] The data demonstrate that the spot-on formulation retained itsefficacy for the thirty-five day period.

Example 4 Long Term Efficacy

[0657] The spot-on formulation according to the first Example 1 (40mg/kg) was applied to four cats infested with fleas and its efficacy forthirty-five days was measured. The results are summarized below Day 1 714 21 28 35 % effic 100 100 100 100 100 99.2

[0658] The data demonstrate that the spot-on formulation retained itsefficacy for the thirty-five day period.

Example 5 Synthesis of t-butyl Nodulisporamide

[0659] A reactor fitted with a stirrer was charged with 4.8 L of MTBEand 1.2 L of THF. Stirring was started and after mixing, 1.11 kg (1.5mol) of nodulisporic acid A, used as a solvate prepared by crystallizingnodulisporic acid A from methanol and acetonitrite in a molar ratio of1:1:1, was added to the to the reactor and allowed to dissolve. Next,0.26 kg HOBT.H₂O (1,70 mol) was charged to the reactor followed by theaddition of 0.35 kg of a melt of DCC (1,70 mol) over a period of 1.5 h,keeping the temperature of the reaction between 20-30° C.

[0660] The mixture was then stirred for 4 h at 20-30° C. Following this,0.27 kg of TBA (3.69 mol) was added over a period of 1 h, again keepingthe temperature of the reaction between 20-30° C. The mixture was thenstirred for 1 h at 20-30° C.

[0661] Following stirring, the reaction mixture was filtered over filtercloth (Dralon) and the cake was washed with 4:1 (v/v) MTBE/THF (3×1.0 L)by means of a passive wash. The cake (DCU) is collected as solid organicwaste (0.28 kg dry weight).

[0662] The filtrates were combined and washed sequentially with 5.0 L of0.5 N aqueous hydrochloric acid and 5.0 L of aqueous saturated sodiumbicarbonate. The washed filtrate (MTBE/THF) was concentrated in vacuo(30° C., 50-100 mBar) to ca. 6.0 L.

[0663] 6.0 L of acetonitrile was added and the solution was concentratedin vacuo to 3.6 L. Water (2.4 L) was then added with stirring to theacetonitrile solution over a period of 2 h at 20-25° C. A yellowprecipitate formed and this was filtered over filter cloth (Dralon) andthen washed with acetonitrile/water (3:2 v/v) (2×1.5L). The solid wasthen air-dried for 3 h at ambient temperature and then in vacuo at40-45° C. to constant weight. The crude t-butyl nodulisporamide wassubsequently recrystallized from acetone/heptane by first dissolving thecrude t-butyl nodulisporamide in 2.5 L of acetone and then adding 5.8 Lof heptane over a 2 h period of time with mechanical stirring at atemperature 20-25° C. The mixture was then aged for 2 h at 20° C.

[0664] The slurry was filtered over filter cloth and the cakesequentially washed with 1:4 (v/v) acetone/heptane (2×1.5L) and heptane(3.0L). The cake was air-dried for 3 h at ambient temperature and thenunder vacuum at 40-45° C. to constant weight to give a molar yield of75% of t-butyl nodulisporamide based upon nodulisporic acid A.

[0665] The above description of the invention is intended to beillustrative and not limiting. Various changes or modifications in theembodiments described herein may occur to those skilled in the art.These can be made without departing from the scope and spirit of theinvention.

What is claimed:
 1. A spot-on formulation for the treatment orprophylaxis of parasite infestation in mammals or birds which comprises(1) an effective amount of at least one nodulisporic acid derivative (2)a pharmaceutically or veterinary acceptable liquid carrier vehicle; and(3) optionally, a crystallization inhibitor.
 2. The spot-on formulationaccording to claim 1, which comprises: (1) an effective amount of atleast one nodulisporic acid derivative of the formula:

wherein R₁ is (1) hydrogen, (2) optionally substituted alkyl, (3)optionally substituted alkenyl, (4) optionally substituted alkynyl, (5)optionally substituted cycloalkyl, (6) optionally substitutedcycloalkenyl, where the substituents on the alkyl, alkenyl, alkynyl,cycloalkyl and cycloalkenyl are 1 to 3 groups independently selectedfrom (i) alkyl, (ii) X-alkyl, where X is O or S(O)_(m), (iii)cycloalkyl, (iv) hydroxy, (v) halogen, (vi) cyano, (vii) carboxy, (viii)NY¹Y², where Y¹ and Y² are independently H or alkyl, (ix) alkanoylamino,and (x) aroylamino wherein said aroyl is optionally substituted with 1to 3 groups independently selected from R^(f), (7) aryl or arylalkylwherein said aryl is optionally substituted with 1 to 3 groupsindependently selected from R^(f), (8) perfluoroalkyl (9) a 5- or6-member heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen atoms optionally substitutedby 1 to 3 groups independently selected from hydroxy, oxo, alkyl andhalogen, and which may be saturated or partly unsaturated, R₂, R₃, andR₄ are independently OR^(a), OCO₂R^(b), OC(O)NR^(c)R^(d); or R₁ and R₂together represent ═O, ═NOR^(a) or ═N—NR^(c)R^(d); R₅ and R₆ are H; orR₅ and R₆ together represent —O—; R₇ is (1) CHO, or (2), the fragment

R₈ is (1) H, (2) OR^(a), or (3) NR^(c)R^(d) R₉ is (1) H, or (2) OR^(a);R₁₀ is (1) CN, (2) C(O)OR^(b), (3) C(O)N(OR^(b))R^(c), (4)C(O)NR^(c)R^(d), (5) NHC(O)OR^(b), (6) NHC(O)NR^(c)R^(d), (7) CH₂OR^(a),(8) CH₂OCO₂R^(b), (9) CH₂OC(O)NR^(c)R^(d), (10) C(O)NRCNR^(c)R^(d), or(11) C(O)NR^(c)SO₂R^(b);

represents a single or a double bond; R^(a) is (1) hydrogen, (2)optionally substituted alkyl, (3) optionally substituted alkenyl, (4)optionally substituted alkynyl, (5) optionally substituted alkanoyl, (6)optionally substituted alkenoyl, (7) optionally substituted alkynoyl,(8) optionally substituted aroyl, (9) optionally substituted aryl, (10)optionally substituted cycloalkanoyl, (11) optionally substitutedcycloalkenoyl, (12) optionally substituted alkylsulfonyl (13) optionallysubstituted cycloalkyl (14) optionally substituted cycloalkenyl wherethe substituents on the alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl,alkynoyl, aroyl, aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl,cycloalkyl and cycloalkenyl are from 1 to 10 groups independentlyselected from the group consisting of hydroxy, alkoxy, cycloalkyl, arylalkoxy, NR^(g)R^(h), CO₂R_(b), CONR^(c)R^(d) and halogen, (15)perfluoroalkyl, (16) arylsulfonyl optionally substituted with 1 to 3groups independently selected from alkyl, perfluoroalkyl, nitro, halogenand cyano, (17) a 5- or 6-member heterocycle containing 1 to 4heteroatoms selected from oxygen, sulfur and nitrogen optionallysubstituted by 1 to 4 groups independently selected from alkyl, alkenyl,perfluoroalkyl, amino, C(O)NR^(c)R^(d), cyano, CO₂R^(b) and halogen, andwhich may be saturated or partly unsaturated; R^(b) is (1) H, (2)optionally substituted aryl, (3) optionally substituted alkyl, (4)optionally substituted alkenyl, (5) optionally substituted alkynyl, (6)optionally substituted cycloalkyl, (7) optionally substitutedcycloalkenyl, or (8) optionally substituted heterocycle containing from1 to 4 heteroatoms independently selected from oxygen, sulfur andnitrogen; where the substituents on the aryl, alkyl, alkenyl,cycloalkyl, cycloalkenyl, heterocycle, or alkynyl are from 1 to 10groups independently selected from (i) hydroxy, (ii) alkyl, (iii) oxo,(iv) SO₂NR^(g)R^(h) (v) arylalkoxy, (vi) hydroxyalkyl, (vii) alkoxy,(viii) hydroxyalkoxy, (ix) aminoalkoxy, (x) cyano, (xi) mercapto, (xii)alkyl-S(O)_(m), (xiii) cycloalkyl optionally substituted with 1 to 4groups independently selected from R^(e), (xiv) cycloalkenyl, (xv)halogen, (xvi) alkanoyloxy, (xvii) C(O)NR^(g)R^(h), (xviii) CO₂R^(i),(xix) formyl, (xx) —NR^(g)R^(h), (xxi) 5 to 9-member heterocycle, whichmay be saturated or partially unsaturated, containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen, andoptionally substituted with 1 to 5 groups independently selected fromR^(e), (xxii) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e), (xxiii) optionally substituted arylalkoxy, wherein the arylsubstituents are 1,2-methylenedioxy or 1 to 5 groups independentlyselected from R^(e), and (xxiv) perfluoroalkyl; R^(c) and R^(d) areindependently selected from R^(b); or R^(c) and R^(d) together with theN to which they are attached form a 3- to 10-member ring containing 0 to2 additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(g),hydroxy, thioxo and oxo; R^(e) is (1) halogen, (2) alkyl, (3)perfluoroalkyl, (4) —S(O)_(m)R^(i), (5) cyano, (6) nitro, (7)R^(i)O(CH₂)_(v)—, (8) R^(i)CO₂(CH₂)_(v)—, (9) R^(i)OCO(CH₂)_(v)—, (10)optionally substituted aryl where the substituents are from 1 to 3 ofhalogen, alkyl, alkoxy, or hydroxy, (11) SO₂NR^(g)R^(h), or (12) amino;R^(f) is (1) alkyl, (2) X-alkyl, where X is O or S(O)_(m), (3) alkenyl,(4) alkynyl, (5) perfluoroalkyl, (6) NY¹Y², where Y¹ and Y² areindependently H or alkyl, (7) hydroxy, (8) halogen, and (9) alkanoylamino, R^(g) and R^(h) are independently (1) hydrogen, (2) alkyloptionally substituted with hydroxy, amino, or CO₂R^(i) (3) aryloptionally substituted with halogen, 1,2-methylenedioxy, alkoxy, alkylor perfluoroalkyl, (4) arylalkyl, wherein the aryl is optionallysubstituted with perfluorolkyl or 1,2-methylenedioxy; (5)alkoxycarbonyl, (6) alkanoyl, (7) alkanoylalkyl, (9) arylalkoxycarbonyl,(10) aminocarbonyl, (11) monoalkylaminocarbonyl (12)dialkylaminocarbonyl; or R^(g) and R^(h) together with the N to whichthey are attached form a 3- to 7-member ring containing 0 to 2additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(e) andoxo; R^(i) is (1) hydrogen, (2) perfluoroalkyl, (3) alkyl, (4)optionally substituted aryl, or arylalkyl, where the aryl substituentsare from 1 to 3 groups independently selected from halogen, alkyl,alkoxy, and hydroxy; m is 0 to 2; and v is 0 to 3; or a pharmaceuticallyacceptable salt thereof; (2) a liquid carrier vehicle comprising asolvent and optionally a cosolvent wherein the solvent is selected fromthe group consisting of acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, dipropylene glycoln-butyl ether, ethanol, isopropanol, methanol, diethylene glycolmonoethyl ether, ethylene glycol monomethyl ether, monomethylaceamide,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol, 2-pyrrolidone, diethylene glycol monoethyl ether,ethylene glycol, diethyl phthalate, and a mixture of at least two ofthese solvents and the cosolvent is selected from the group consistingof absolute ethanol, isopropanol or methanol; (3) optionally, acrystallization inhibitor selected from the group consisting of ananionic surfactant, a cationic surfactant, a non-ionic surfactant, anamine salt, an amphoteric surfactant, polyvinylpyrrolidone, polyvinylalcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethyleneglycols, benzyl alcohol, mannitol, glycerol, sorbitol,polyoxyethylenated sorbitan esters; lecithin, sodiumcarboxymethylcellulose, and acrylic derivatives, or a mixture of thesecrystallization inhibitors.
 3. The spot-on formulation according toclaim 2 wherein R₁ is (1) hydrogen, (2) optionally substituted alkyl,(3) optionally substituted alkenyl, (4) optionally substituted alkynyl,(5) optionally substituted cycloalkyl, (6) optionally substitutedcycloalkenyl where the substituents on the alkyl, alkenyl, alkynyl,cycloalkyl and cycloalkenyl are 1 to 3 groups independently selectedfrom (i) alkyl, (ii) X-alkyl, where X is O or S(O)_(m), (iii)cycloalkyl, (iv) hydroxy, (v) halogen, (vi) cyano, (vii) carboxy, and(viii) NY¹Y², where Y¹ and Y² are independently H or alkyl, (7) arylalkyl wherein said aryl is optionally substituted with 1 to 3 groupsindependently selected from R^(f), (8) perfluoroalkyl, (9) a 5- or6-member heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen atoms optionally substitutedby 1 to 3 groups independently selected from hydroxy, oxo, alkyl andhalogen, and which may be saturated or partly unsaturated, R₈ is (1) H,(2) OH, or (3) NH₂; R₉ is (1) H or (2) OH; R₁₀ is (1) C(O)OR^(b), (2)C(O)N(OR^(b))R^(c), (3) C(O)NR^(c)R^(d), (4) NHC(O)OR^(b), (5)NHC(O)NR^(c)R^(d), (6) CH₂OR^(a), (7) CH₂OCO₂R^(b), (8)CH₂OC(O)NR^(c)R^(d), (9) C(O)NR^(c)NR^(c)R^(d), or (10)C(O)NR^(c)SO₂R^(b); R^(a) is (1) hydrogen, (2) optionally alkyl, (3)optionally substituted alkenyl, (4) optionally substituted alkynyl, (5)optionally substituted alkanoyl, (6) optionally substituted alkenoyl,(7) optionally substituted alkynoyl, (8) optionally substituted aroyl,(9) optionally substituted aryl, (10) optionally substitutedcycloalkanoyl, (11) optionally substituted cycloalkenoyl, (12)optionally substituted alkylsulfonyl (13) optionally substitutedcycloalkyl (14) optionally substituted cycloalkenyl where thesubstituents on the alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl,alkynoyl, aroyl, aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl,cycloalkyl and cycloalkenyl are from 1 to 10 groups independentlyselected from hydroxy, alkoxy, cycloalkyl, aryl alkoxy, NR^(g)R^(h),CO₂R^(b), CONR^(c)R^(d) and halogen, (15) perfluoroalkyl, (16)arylsulfonyl optionally substituted with 1 to 3 groups independentlyselected from alkyl, perfluoroalkyl, halogen and cyano, (17) a 5- or6-member heterocycle containing 1 to 4 heteroatoms selected from oxygen,sulfur and nitrogen optionally substituted by 1 to 4 groupsindependently selected from alkyl, alkenyl, perfluoroalkyl, amino,C(O)NR^(c)R^(d), cyano, CO₂R^(b) and halogen, and which may be saturatedor partly unsaturated; R^(b) is (1) H, (2) optionally substituted aryl,(3) optionally substituted alkyl, (4) optionally substituted alkenyl,(5) optionally substituted alkynyl, (6) optionally substitutedcycloalkyl, (7) optionally substituted cycloalkenyl, or (8) optionallysubstituted 5- to 10-member heterocycle containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen;where the substituents on the aryl, alkyl, alkenyl, cycloalkyl,cycloalkenyl, heterocycle, or alkynyl are from 1 to 10 groupsindependently selected from (i) hydroxy, (ii) alkyl, (iii) oxo, (iv)SO₂NR^(g)R^(h), (v) arylalkoxy, (vi) hydroxyalkyl, (vii) alkoxy, (viii)hydroxyalkoxy, (ix) aminoalkoxy, (x) cyano, (xi) perfluoroalkyl, (xii)alkyl-S(O)_(m), (xiii) cycloalkyl optionally substituted with 1 to 4groups independently selected from R^(e), (xiv) cycloalkenyl, (xv)halogen, (xvi) alkanoyloxy, (xvii) C(O)NR^(g)R^(h), (xviii) CO₂R^(i),(xix) optionally substituted aryl alkoxy, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e), (xx) —NR^(g)R^(h), (xxi) 5 to 6-member heterocycle, which may besaturated or partially unsaturated, containing from 1 to 4 heteroatomsindependently selected from oxygen, sulfur and nitrogen, and optionallysubstituted with 1 to 5 groups independently selected from R^(e), and(xxii) optionally substituted aryl, wherein the aryl substituents are1,2-methylenedioxy or 1 to 5 groups independently selected from Re;R^(e) is (1) halogen, (2) alkyl, (3) perfluoroalkyl, (4) —S(O)_(m)R^(i),(5) cyano, (6) amino, (7) R^(i)O(CH₂)^(v)—, (8) R^(i)CO₂(CH₂)^(v)—, (9)R^(i)OCO(CH₂)_(v)—, (10) optionally substituted aryl where thesubstituents are from 1 to 3 of halogen, alkyl, alkoxy, or hydroxy, or(11) SO₂NR^(g)R^(h); R^(f) is (1) methyl, (2) X-alkyl, where X is O orS(O)^(m), (3) halogen, (4) acetylamino, (5) trifluoromethyl, (6) NY¹Y²,where Y¹ and Y² are independently H or methyl, and (7) hydroxy; R^(g)and R^(h) are independently (1) hydrogen, (2) alkyl optionallysubstituted with hydroxy, amino, or CO₂R^(i) (3) aryl optionallysubstituted with halogen, 1,2-methylenedioxy, alkoxy, alkyl orperfluoroalkyl, (4) aryl alkyl, wherein the aryl is optionallysubstituted with perfluorolkyl or 1,2-methylenedioxy; (5)alkoxycarbonyl, (6) alkanoyl, (7) alkanoylalkyl, (9) arylalkoxycarbonyl,(10) aminocarbonyl, (11) monoalkylaminocarbonyl (12)dialkylaminocarbonyl; or R^(g) and R^(h) together with the N to whichthey are attached form a 5- to 6 membered ring containing 0 to 2additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(e) andoxo; R^(i) is (1) hydrogen, (2) perfluoroalkyl, (3) alkyl, (4)optionally substituted aryl alkyl, where the aryl substituents are from1 to 3 groups independently selected from halogen, alkyl, alkoxy, andhydroxy.
 4. The spot-on formulation according to claim 2, wherein R¹ is(1) hydrogen, (2) optionally substituted alkyl, (3) optionallysubstituted alkenyl, (4) optionally substituted alkynyl, where thesubstituents on the alkyl, alkenyl, and alkynyl are 1 to 3 groupsindependently selected from (i) methyl, (ii) X-methyl, where X is O orS(O)_(m) and (iii) halogen, (5) arylalkyl wherein said aryl isoptionally substituted with 1 to 3 groups independently selected fromR^(f). (6) trifluoromethyl R₈ is (1) H, (2) OH, or (3) NH₂ R^(g) is (1)H, or (2) OH; R₁₀ is (1) C(O)OR^(b), (2) C(O)N(OR^(b))R^(c), (3)C(O)NR^(c)R^(d), (4) NHC(O)OR^(b), (5) NHC(O)NR^(c)R^(d), (6) CH₂OR^(a),(7) CH₂OCO₂R^(b), (8) CH₂OC(O)NR^(c)R^(d), (9) C(O)NR^(c)NR^(c)R^(d), or(10) C(O)NR^(c)SO₂R^(b); R^(a) is (1) hydrogen, (2) optionallysubstituted alkyl, (3) optionally substituted alkenyl, (4) optionallysubstituted alkynyl, (5) optionally substituted alkanoyl, (6) optionallysubstituted aroyl, (7) optionally substituted cycloalkanoyl, (8)optionally substituted cycloalkenoyl, (9) optionally substitutedalkylsulfonyl where the substituents on the alkyl, alkenyl, alkynyl,alkanoyl, aroyl, cycloalkanoyl, cycloalkenoyl, and alkylsulfonyl, arefrom 1 to 5 groups independently selected from hydroxy, alkoxy, arylalkoxy, NR^(g)R^(h), CO₂R^(b), CONR^(c)R^(d) and halogen, (10)trifluoromethyl, (11) arylsulfonyl optionally substituted with 1 to 3groups independently selected from methyl, trifluoromethyl and halogen,(12) a 5- or 6-member heterocycle containing 1 to 4 heteroatoms selectedfrom oxygen, sulfur and nitrogen optionally substituted by 1 to 4 groupsindependently selected from methyl, trifluoromethyl, C(O)NR^(c)R^(d),CO₂R^(b) and halogen, and which may be saturated or partly unsaturated;R^(b) is (1) H, (2) optionally substituted aryl, (3) optionallysubstituted alkyl, (4) optionally substituted alkenyl, (5) optionallysubstituted alkynyl, (6) optionally substituted cycloalkyl, (7)optionally substituted cycloalkenyl, or (8) optionally substituted 5- to6-member heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen; where the substituents on thearyl, alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, or alkynylare from 1 to 10 groups independently selected from (i) hydroxy, (ii)alkyl, (iii) oxo, (iv) SO₂NR^(g)R^(h), (v) arylalkoxy, (vi)hydroxyalkyl, (vii) alkoxy, (viii) hydroxyalkoxy, (ix) aminoalkoxy, (x)cyano, (xi) alkyl-S(O)_(m), (xii) cycloalkyl optionally substituted with1 to 4 groups independently selected from R^(e), (xiii) cycloalkenyl,(xiv) halogen, (xv) alkanoyloxy, (xvi) C(O)NR^(g)R^(h), (xvii) CO₂R^(i),(xvii) —NR^(g)R^(h), (xix) 5 to 6-member heterocycle, which may besaturated or partially unsaturated, containing from 1 to 4 heteroatomsindependently selected from oxygen, sulfur and nitrogen, and optionallysubstituted with 1 to 5 groups independently selected from R^(e), (xx)optionally substituted aryl, wherein the aryl substituents are1,2-methylenedioxy or 1 to 5 groups independently selected from R^(e),(xxi) optionally substituted aryl alkoxy, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e), and (xxii) perfluoroalkyl; R^(e) is (1) halogen, (2) alkyl, (3)perfluoroalkyl, (4) —S(O)_(m)R^(i), (5) cyano, (6) R^(i)O(CH₂)_(v)—, (7)R^(i)CO₂(CH₂)^(v)—, (8) R^(i)OCO(CH₂)_(v)—, (9) optionally substitutedaryl where the substituents are from 1 to 3 of halogen, alkyl, alkoxy,or hydroxy, (10) SO₂NR^(g)R^(h), or (11) amino; R^(f) is (1) methyl, (2)X-alkyl, where X is O or S(O)_(m), (3) trifluoromethyl, (4) NY¹Y², whereY¹ and Y² are independently H or methyl, (5) hydroxy, (6) halogen, and(7) acetylamino, R^(g) and R^(h) are independently (1) hydrogen, (2)alkyl optionally substituted with hydroxy, amino, or CO₂R^(i) (3) aryloptionally substituted with halogen, 1,2-methylenedioxy, alkoxy, alkylor perfluoroalkyl, (4) aryl or arylalkyl, wherein the aryl is optionallysubstituted with perfluorolkyl or 1,2-methylenedioxy; (5)alkoxycarbonyl, (6) alkanoyl, (7) alkanoylalkyl, (9) arylalkoxycarbonyl,(10) aminocarbonyl, (11) monoalkylaminocarbonyl (12)dialkylaminocarbonyl; or R^(g) and R^(h) together with the N to whichthey are attached form a 5- to 6-member ring containing 0 to 2additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(e) andoxo; R^(i) is (1) hydrogen, (2) perfluoroalkyl, (3) alkyl, (4)optionally substituted aryl or arylalkyl, where the aryl substituentsare from 1 to 3 groups independently selected from halogen, alkyl,alkoxy, and hydroxy.
 5. The spot-on formulation according to claim 2,wherein R₁₀ is C(O)NR^(c)R^(d); R^(b) is (1) hydrogen, (2) optionallysubstituted aryl, (3) optionally substituted alkyl, (4) optionallysubstituted alkenyl, (5) optionally substituted alkynyl, (6) optionallysubstituted cycloalkyl, (7) optionally substituted cycloalkenyl, or (8)optionally substituted 5 to 6-member heterocycle containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen;where the substituents on the aryl, alkyl, alkenyl, cycloalkyl,cycloalkenyl, heterocycle, or alkynyl are from 1 to 10 groupsindependently selected from the group consisting of (i) hydroxy, (ii)alkyl, (iii) oxo, (iv) SO₂NR^(g)R^(h), (v) arylalkyl, (vi)hydroxyalkylfoxy, (viii) hydroxyalkoxy, (ix) aminoalkoxy, (x) cyano,(xi) perfluoroalkyl, (xii) alkyl-S(O)^(m), (xiii) cycloalkyl optionallysubstituted with 1 to 4 groups selected from R^(e), (xiv) cycloalkenyl,(xv) halogen, (xvi) C(O)NR^(g)R^(h), (xvii) CO₂R^(i), (xviii)—NR^(g)R^(h), (xix) 5 to 9-member heterocycle containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen, andoptionally substituted with 1 to 3 groups independently selected fromR^(e), (xx) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e) and (xxi) optionally substituted aryl alkoxy, wherein the arylsubstituents are 1,2-methylenedioxy or 1 to 5 groups independentlyselected from R^(e); R^(c) and R^(d) are independently selected fromR^(b); or R^(c) and R^(d) together with the N to which they are attachedform a 3- to 10-member ring containing 0 to 2 additional heteratomsselected from O, S(O)_(m), and N, optionally substituted with 1 to 3groups independently selected from R^(g), hydroxy, thioxo and oxo; R^(e)is (1) halogen, (2) alkyl, (3) perfluoroalkyl, (4) R^(i)O(CH₂)^(v)—, (5)R^(i)CO₂(CH₂)^(v)—, (6) R^(i)OCO(CH₂)_(v)—, (7) SO₂NR^(g)R^(h); (8)amino v is 0; R^(g) and R^(h) are independently (1) hydrogen, (2) alkyloptionally substituted with hydroxy, amino, or CO₂R^(i), (3) aryloptionally substituted with halogen, 1,2-methylenedioxy, alkoxy, alkylor perfluoroalkyl, (4) aryl or arylalkyl, wherein the aryl is optionallysubstituted with perfluoroalkyl or 1,2-methylenedioxy, (5)alkoxycarbonyl, (6) alkanoyl, (7) arylalkoxycarbonyl, (8) aminocarbonyl,or R^(g) and R^(h) together with the N to which they are attached form a5- to 6-member ring containing 0 to 2 additional heteroatoms selectedfrom O, S(O)_(m), and N, optionally substituted with 1 to 3 groupsindependently selected from R^(e) and oxo; R^(i) is (1) hydrogen or (2)optionally substituted alkyl wherein the substituents are aryl orsubstituted aryl, and the aryl substituents are from 1 to 3 groupsindependently selected from halogen, alkyl, alkoxy, and hydroxy.
 6. Thespot-on formulation according to claim 2, wherein the nodulisporic acidderivative is a compound of the formula

wherein R^(x) is selected from the group consisting of: H, CH₃, CH₂CH₃,C(CH₃)₃, CH₂CH₂CH₃, CH₂CH₂OH, CH(CO₂CH₃)CH₂OH, CH₂CO₂CH₃,CH₂CH(OCH₂CH₃)₂, CH₂CH₂OCH₂CH₂OH, CH(CH₃)(CH₂)₃C(CH₃)₂OH, (CH₂)₃OH,(CH₂)₄OH, (CH₂)SOH, CH(CH₂OH)CH₂CH₃, NHC(CH₃)₃, CH₂CN, (CH₂)₆OH,CH₂CH(OH)CH₃, CH(CH₂OH)CH₂CH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃, CH₂CONH₂,CH(CH₃)(CH₂OH)₂, CH₂CH₂NHCH₂CH₂OH, CH(CH₂OH)(CH₂)₃CH₃, CH(CH₂OCH₃)CH₃,(CH₂)₂SH, (CH₂)₄NH₂, CH₂CH₂SO₂CH₃, CH₂CH₂S(O)CH₃, CH(CH(CH₃)₂)CH₂OH,(CH₂)₃NH₂, (CH₂)₃N(CH₂CH₃)₂, (CH₂)₃N(CH₃)₂, OCH₂CH₃, CH₂CH(OH)CH₂OH,OCH₃, CH₂CH₂OCH₃, CH₂CH₂NHC(O)CH₃, C(CH₃)₂CH₂OH, c-C₃H₅, cC₆H₁₁,(CH₂)₃OCH₂CH₃, CH₂CH═CH₂, C(CH₂CH₃)(CH₂OH)₂, CH₂C≡CH, CH₂CO₂CH₂CH₃,CH₂CH₂F, (CH₂)₃O(CH₂)₁₁CH₃, CH₂CH₂N(CH₃)₂, CH₂CH₂OCH₂CH₂NH₂, CH₂CF₃,NHCH₂CO₂CH₂CH₃, CH(CH₃)CO₂CH₃, C(CH₃)₂CH₂C(O)CH₃, CH(CO₂CH₂CH₃)₂,CH₂CH₃, CH(CH₂CH₂CH₃)CO₂CH₃, CH₂CH₂CH₂OCH₃, C(CH₃)₂CH₂C≡CH, (CH₂)₄CH₃,CH(CH₂CH₂CH₃)₂, (CH₂)SCH₃, CH₂CH₂CO₂H, CH(CH(CH₃)₂)CO₂CH₃, OCH₂CO₂H,CH(CH(CH₃)₂)CH₂OH, CH(CH(CH₃)₂)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)CH₂OH,CH(CH₃)₂, (CH₂)CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)OH, (CH₂)₃CH₃,(CH₂)₂OCH₂CH₃, 1-adamantyl, (CH₂)₈CH₃, CH(CH₃)CH(CH₃)₂, (CH₂)₃NHCH₃,(CH₂)₂N(CH₂CH₃)₂,


7. The spot-on formulation according to claim 6, wherein R^(x) isC(CH₃)₃.
 8. The spot-on formulation according to claim 1, wherein theliquid carrier vehicle comprises a microemulsion.
 9. The spot-onformulation according to claim 6, wherein the liquid carrier vehiclefurther comprises an excipient.
 10. The spot-on formulation according toclaim 9, wherein the excipient is C₈-C₁₀ caprylic/capric triglycerides,oleic acid or propylene glycol.
 11. The spot-on formulation according toclaim 10, wherein the spot-on formulation further comprises anantioxidant.
 12. The spot-on formulation according to claim 11, whereinthe antioxidant is selected from the group consisting of butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, and sodium thiosulphate.
 13. The spot-onformulation according to claim 12, wherein the compound of formula (I)is t-butyl nodulisporamide, the carrier medium comprises diethyleneglycol monoethyl ether and C₈-C₁₀ caprylic/capric triglycerides, and theantioxidant is butylated hydroxytoluene.
 14. The spot-on formulationaccording to claim 2, wherein the combination comprises about 0.001 toabout 100 mg/kg of weight of mammal or bird of a compound of formula(I).
 15. The spot-on formulation according to claim 7, wherein thecombination comprises about 1 to about 50 mg/kg of weight of mammal orbird of a compound of formula (I).
 16. The spot-on formulation accordingto claim 2, which comprises crystallization inhibitor and furthercomprises an antioxidant.
 17. The spot-on formulation wherein thecompound of formula (I) is t-butyl nodulisporamide.
 18. The spot-onformulation according to claim 16, wherein about 0.005 to about 1% (W/V)of antioxidant is present and the antioxidant is selected from the groupconsisting of butylated hydroxyanisole, butylated hydroxytoluene,ascorbic acid, sodium metabisulphite, propyl gallate, and sodiumthiosulphate.
 19. The spot-on formulation according to claim 18, whereinthe crystallization inhibitor is present in an amount from about 1 toabout 20% W/V.
 20. The spot-on formulation according to claim 19,wherein the anionic surfactant is alkaline stearates, sodium abietate;alkyl sulphates; sodium dodecylbenzenesulphonate, sodiumdioctylsulphosuccinate; and fatty acids; the cationic surfactant iswater-soluble quaternary ammonium salts of formula N⁺R′R″R′″R″″ Y⁻ inwhich the radicals R independently are hydrocarbon radicals, optionallyhydroxylated, and Y⁻ is an anion of a strong acid; the amine salt is anamine salt of N⁺R′R″R′″ in which the radicals R independently areoptionally hydroxylated hydrocarbon radicals; the non-ionic surfactantis optionally polyoxyethylenated sorbitan esters, polyoxyethylenatedalkyl ethers; polyethylene glycol stearate, polyoxyethylenatedderivatives of castor oil, polyglycerol esters, polyoxyethylenated fattyalcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxideand propylene oxide; and the amphoteric surfactant is lauryl-substitutedbetaine compounds.
 21. The spot-on formulation according to claim 19,where the crystallization inhibitor is a crystallization inhibitorsystem comprising a polymeric film-forming agent and a surfactant. 22.The spot-on formulation according to claim 21, wherein the polymericfilm-forming agent is polyvinylpyrrolidone, polyvinyl alcohols, or acopolymer of vinyl acetate and polyvinylpyrrolidone and the surfactantis a non-ionic surfactant.
 23. The spot-on formulation according toclaim 22, wherein the crystallization inhibitor system is a mixture ofpolyvinylpyrrolidone and polyoxethylene (20) sorbitan mono-oleate. 24.The spot-on formulation according to claim 18, wherein the compound offormula (I) is t-butyl nodulisporamide, the liquid carrier vehicle isdiethylene glycol monoethyl ether, the crystallization inhibitor ispyrrolidone and the antioxidant is butylated hydroxytoluene.
 25. Amethod of treating parasite infestations or for the prophylaxis ofparasite infestation in mammals, fish or birds which comprises applyingto said mammals, fish or birds an effective amount of a spot-oncomposition according to claim
 1. 26. The method according to claim 25,wherein the parasite is an ectoparasite.
 27. The method according toclaim 25, wherein the parasite is an endoparasite.
 28. The methodaccording to claim 25, wherein the mammal is a cat, dog, horse, cattleor sheep.
 29. The method according to claim 28, wherein the parasite isa flea or tick.
 30. The method according to claim 25, wherein the mammalis a human.
 31. The method according to claim 25, wherein theectoparasites are mites, ticks, mosquitoes, flies or a combination ofthe foregoing.
 32. A method of treating parasite infestations or for theprophylaxis of parasite infestations in mammals or birds which comprisesapplying to said mammals or birds an effective amount of a spot-onformulation according to claim
 13. 33. The method according to claim 32wherein the parasite is a flea or tick and the mammal is a cat or dog.34. The method of claim 25, wherein the administration is bimonthly. 35.The method of claim 25, wherein the administration is quarterly.
 36. Themethod of claim 25, wherein the administration is monthly.
 37. A methodfor treating parasite infestations or for the prophylaxis of parasiteinfestations in mammals or birds which comprises applying to said mammalor bird an effective amount of a spot-on formulation according to claim24.
 38. The method according to claim 37 wherein the mammal is a cat ordog and the parasite is a flea or tick.
 39. The method of claim 37,wherein the administration is bimonthly.
 40. The method of claim 37,wherein the administration is quarterly.
 41. The method of claim 37,wherein the administration is monthly.
 42. A spot-on formulation forcombating parasites in a mammal which comprises applying a compositionaccording to claim 6 for a localized cutaneous application to saidmammal with absorption and a resultant plasma concentration of thecompound(s) of formula (I) wherein the liquid carrier vehicle comprisesdiethylene glycol monoethyl ether, and at least one antioxidant.
 43. Thespot-on formulation according to claim 42 which further comprises acrystallization inhibitor.
 44. The spot-on formulation as claimed inclaim 43, wherein an antioxidant is BHT and the crystallizationinhibitor is pyrrolidone.
 45. A method for combating parasites in amammal comprising topically administering to a mammal a parasiticicallyeffective amount of a spot-on formulation according to claim
 42. 46. Themethod according to claim 45, wherein the mammal is a cat or dog and theparasite is a flea or tick.
 47. A method for obtaining a detectableplasma concentration of parasiticides in a mammal comprising topicallyapplying to a localized area on said mammal a parasiticically effectiveamount of the spot-on formulation as claimed in claim
 42. 48. A methodfor combating parasites of a cat or dog comprising localized cutaneousapplication to the cat or dog, between the shoulders, at a frequency notgreater than monthly, of a spot-on composition, which comprises, in aveterinarily acceptable vehicle, an effect amount parasiticallyeffective amount of at least one of the formula

wherein R^(x) is selected from the group consisting of: H, CH₃, CH₂CH₃,C(CH₃)₃, CH₂CH₂CH₃, CH₂CH₂OH, CH(CO₂CH₃)CH₂OH, CH₂CO₂CH₃,CH₂CH(OCH₂CH₃)₂, CH₂CH₂OCH₂CH₂OH, CH(CH₃)(CH₂)₃C(CH₃)₂OH, (CH₂)₃OH,(CH₂)₄OH, (CH₂)SOH, CH(CH₂OH)CH₂CH₃, NHC(CH₃)₃, CH₂CN, (CH₂)₆OH,CH₂CH(OH)CH₃, CH(CH₂OH)CH₂CH₂CH₃, CH₂CH₂SCH₃, CH₂CH₂SCH₂CH₃, CH₂CONH₂,CH(CH₃)(CH₂OH)₂, CH₂CH₂NHCH₂CH₂OH, CH(CH₂OH)(CH₂)₃CH₃, CH(CH₂OCH₃)CH₃,(CH₂)₂SH, (CH₂)₄NH₂, CH₂CH₂SO₂CH₃, CH₂CH₂S(O)CH₃, CH(CH(CH₃)₂)CH₂OH,(CH₂)₃NH₂, (CH₂)₃N(CH₂CH₃)₂, (CH₂)₃N(CH₃)₂, OCH₂CH₃, CH₂CH(OH)CH₂OH,OCH₃, CH₂CH₂OCH₃, CH₂CH₂NHC(O)CH₃, C(CH₃)₂CH₂OH, c-C₃H₅, cC₆H₁₁,(CH₂)₃OCH₂CH₃, CH₂CH═CH₂, C(CH₂CH₃)(CH₂OH)₂, CH₂C≡CH, CH₂CO₂CH₂CH₃,CH₂CH₂F, (CH₂)₃O(CH₂)₁₁CH₃, CH₂CH₂N(CH₃)₂, CH₂CH₂OCH₂CH₂NH₂, CH₂CF₃,NHCH₂CO₂CH₂CH₃, CH(CH₃)CO₂CH₃, C(CH₃)₂CH₂C(O)CH₃, CH(CO₂CH₂CH₃)₂,CH₂CH₃, CH(CH₂CH₂CH₃)CO₂CH₃, CH₂CH₂CH₂OCH₃, C(CH₃)₂CH₂C≡CH, (CH₂)₄CH₃,CH(CH₂CH₂CH₃)₂, (CH₂)SCH₃, CH₂CH₂CO₂H, CH(CH(CH₃)₂)CO₂CH₃, OCH₂CO₂H,CH(CH(CH₃)₂)CH₂OH, CH(CH(CH₃)₂)CH₂OH, CH(CH₃)CH₂OH, CH(CH₃)CH₂OH,CH(CH₃)₂, (CH₂)CH(CH₃)₂, CH(CH₃)CH₂CH₃, CH₂CH(CH₃)OH, (CH₂)₃CH₃,(CH₂)₂OCH₂CH₃, 1-adamantyl, (CH₂)₈CH₃, CH(CH₃)CH(CH₃)₂, (CH₂)₃NHCH₃,(CH₂)₂N(CH₂CH₃)₂, the vehicle is for a localized cutaneous applicationto the animal between the shoulders and contains an organic solvent, anantioxidant and/or a crystallization inhibitor wherein: the organicsolvent comprises acetone, ethyl acetate, methanol, ethanol,isopropanol, dimethylformamide, dichloromethane or diethyl glycolmonoethyl ether; said solvent optionally supplemented by Cs-C₁₀caprylic/capric triglyceride, oleic acid or propylene glycol; theantioxidant is selected from the group consisting of butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisuphite, propylgallate, and sodium theosulphate; and thecrystallization inhibitor selected from the group consisting ofpolyvinylpyrrolidone, copolymers of vinyl acetate and vinylpyrrolidone,polyoxyethylenated sorbitan esters and mixtures thereof; whereby thereis a prolonged release of formula (I) in or on the body of the cat ordog.
 49. The method of claim 48 wherein in the spot-on composition thecompound of formula (I) is t-butyl nodulisporamide.
 50. The method ofclaim 48 wherein compound of formula (I) is present in the spot-oncomposition in an amount of from about 0.1 to about 100 mg/kg of weightof animal.
 51. The method according to claim 49 wherein the liquidcarrier vehicle is diethylene glycol monoethyl ether and the antioxidantis butylated hydroxytoluene.
 52. The method of claim 49 wherein thespot-on composition comprises an antioxidant and the antioxidant ispolyvinylpyrrolidone.
 53. A process for the preparation of a compoundhaving the formula:

wherein R₁ is (1) hydrogen, (2) optionally substituted alkyl, (3)optionally substituted alkenyl, (4) optionally substituted alkynyl, (5)optionally substituted cycloalkyl, (6) optionally substitutedcycloalkenyl, where the substituents on the alkyl, alkenyl, alkynyl,cycloalkyl and cycloalkenyl are 1 to 3 groups independently selectedfrom (i) alkyl, (ii) X-alkyl, where X is O or S(O)_(m), (iii)cycloalkyl, (iv) hydroxy, (v) halogen, (vi) cyano, (vii) carboxy, (viii)NY¹Y², where Y¹ and Y² are independently H or alkyl, (ix) alkanoylamino,and (x) aroylamino wherein said aroyl is optionally substituted with 1to 3 groups independently selected from R^(f) (7) aryl or arylalkylwherein said aryl is optionally substituted with 1 to 3 groupsindependently selected from R^(f), (8) perfluoroalkyl (9) a 5- or6-member heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen atoms optionally substitutedby 1 to 3 groups independently selected from hydroxy, oxo, alkyl andhalogen, and which may be saturated or partly unsaturated, R₂, R₃, andR₄ are independently OR^(a), OCO₂R^(b), OC(O)NR^(c)R^(d); or R₁ and R₂represent ═O, ═NOR^(a) or ═N—NR^(c)R^(d); R^(a) is (1) hydrogen, (2)optionally substituted alkyl, (3) optionally substituted alkenyl, (4)optionally substituted alkynyl, (5) optionally substituted alkanoyl, (6)optionally substituted alkenoyl, (7) optionally substituted alkynoyl,(8) optionally substituted aroyl, (9) optionally substituted aryl, (10)optionally substituted cycloalkanoyl, (11) optionally substitutedcycloalkenoyl, (12) optionally substituted alkylsulfonyl (13) optionallysubstituted cycloalkyl (14) optionally substituted cycloalkenyl wherethe substituents on the alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl,alkynoyl, aroyl, aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl,cycloalkyl and cycloalkenyl are from 1 to 10 groups independentlyselected from the group consisting of hydroxy, alkoxy, cycloalkyl, arylalkoxy, NR^(g)R^(h), CO₂R^(b), CONR^(c)R^(d) and halogen, (15)perfluoroalkyl, (16) arylsulfonyl optionally substituted with 1 to 3groups independently selected from alkyl, perfluoroalkyl, nitro, halogenand cyano, (17) a 5- or 6-member heterocycle containing 1 to 4heteroatoms selected from oxygen, sulfur and nitrogen optionallysubstituted by 1 to 4 groups independently selected from alkyl, alkenyl,perfluoroalkyl, amino, C(O)NR^(c)R^(d), cyano, CO₂R^(b) and halogen, andwhich may be saturated or partly unsaturated; R^(b) is (1) H, (2)optionally substituted aryl, (3) optionally substituted alkyl, (4)optionally substituted alkenyl, (5) optionally substituted alkynyl, (6)optionally substituted cycloalkyl, (7) optionally substitutedcycloalkenyl, or (8) optionally substituted heterocycle containing from1 to 4 heteroatoms independently selected from oxygen, sulfur andnitrogen; where the substituents on the aryl, alkyl, alkenyl,cycloalkyl, cycloalkenyl, heterocycle, or alkynyl are from 1 to 10groups independently selected from (i) hydroxy, (ii) alkyl, (iii) oxo,(iv) SO₂NR^(g)R^(h), (v) arylalkoxy, (vi) hydroxyalkyl, (vii) alkoxy,(viii) hydroxyalkoxy, (ix) aminoalkoxy, (x) cyano, (xi) mercapto, (xii)alkyl-S(O)_(m), (xiii) cycloalkyl optionally substituted with 1 to 4groups independently selected from R^(e), (xiv) cycloalkenyl, (xv)halogen, (xvi) alkanoyloxy, (xvii) C(O)NR^(g)R^(h), (xviii) CO₂R^(i),(xix) formyl, (xx) —NR^(g)R^(h), (xxi) 5 to 9-member heterocycle, whichmay be saturated or partially unsaturated, containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen, andoptionally substituted with 1 to 5 groups independently selected fromR^(e), (xxii) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e), (xxiii) optionally substituted arylalkoxy, wherein the arylsubstituents are 1,2-methylenedioxy or 1 to 5 groups independentlyselected from R^(e), and (xxiv) perfluoroalkyl; R^(c) and R^(d) areindependently selected from R^(b); or R^(c) and R^(d) together with theN to which they are attached form a 3- to 10-member ring containing 0 to2 additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(g),hydroxy, thioxo and oxo; R^(e) is (1) halogen, (2) alkyl, (3)perfluoroalkyl, (4) —S(O)_(m)R^(i), (5) cyano, (6) nitro, (7)R^(i)O(CH₂)_(v)—, (8) R^(i)CO₂(CH₂)_(v)—, (9) R^(i)OCO(CH₂)_(v)—, (10)optionally substituted aryl where the substituents are from 1 to 3 ofhalogen, alkyl, alkoxy, or hydroxy, (11) SO₂NR^(g)R^(h), or (12) amino;R^(f) is (1) alkyl, (2) X-alkyl, where X is O or S(O)_(m), (3) alkenyl,(4) alkynyl, (5) perfluoroalkyl, (6) NY¹Y², where Y¹ and Y² areindependently H or alkyl, (7) hydroxy, (8) halogen, and (9) alkanoylamino, R^(g) and R^(h) are independently (1) hydrogen, (2) alkyloptionally substituted with hydroxy, amino, or CO₂R^(i) (3) aryloptionally substituted with halogen, 1,2-methylenedioxy, alkoxy, alkylor perfluoroalkyl, (4) arylalkyl, wherein the aryl is optionallysubstituted with perfluorolkyl or 1,2-methylenedioxy; (5)alkoxycarbonyl, (6) alkanoyl, (7) alkanoylalkyl, (9) arylalkoxycarbonyl,(10) aminocarbonyl, (11) monoalkylaminocarbonyl (12)dialkylaminocarbonyl; or R^(g) and R^(h) together with the N to whichthey are attached form a 3- to 7-member ring containing 0 to 2additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(e) andoxo; R^(i) is (1) hydrogen, (2) perfluoroalkyl, (3) alkyl, (4)optionally substituted aryl, or arylalkyl, where the aryl substituentsare from 1 to 3 groups independently selected from halogen, alkyl,alkoxy, and hydroxy; m is 0 to 2; and v is 0 to 3; R⁵¹ is R^(c) andR^(d) or a pharmaceutically acceptable salt thereof which comprises (1)coupling a compound of formula II′:

wherein R₁, R₂, R₃, and R⁴ are defined above, with a compound of formulaIII: R^(6′)—N═C═N—R^(7′)  III wherein R^(6′) and R^(7′) can beindependently selected from alkyl and cycloalkyl, in the presence of anorganic solvent to produce a first intermediate compound, of the formula

(2) reacting the first intermediate compound with an activatingcompound, Act to produce a second intermediate compound of the formula:

(3) adding an alkyl amine of the formula HNR^(c)R^(d) to the secondintermediate compound to obtain a compound of formula I′.
 54. Theprocess according to claim 53, wherein the activating compound is1-hydroxybenzotriazole, 2-hydroxypyridine-N-oxide, 2-hydroxypyridine andhydroxysuccinimide.
 55. The process according to claim 53 wherein thefirst intermediate compound has the formula

wherein R^(6′) and R^(7′) can be independently selected from alkyl andcycloalkyl, or a pharmaceutically acceptable salt thereof.
 56. Theprocess according to claim 53 wherein the second intermediate compoundhas the formula

or a pharmaceutically acceptable salt thereof.
 57. The process accordingto claim 53 wherein said organic solvent is a halogenated hydrocarbon ora mixture of halogenated hydrocarbons.
 58. The process according toclaim 53 wherein said organic solvent is an ether or a mixture ofethers.
 59. The process according to claim 56 wherein said halogenatedhydrocarbon is methlyene chloride.
 60. The process according to claim 57wherein said ether or mixture of ethers are selected from the groupconsisting of tetrahydrofuran, diethyl ether, and methyl t-butyl ether.61. The process according to claim 52 wherein the process is which iscarried out in a single step without the isolation of a first and secondintermediate compounds.
 62. The process according to claim 53 which iscarried out step-wise with the isolation of a first and/or secondintermediate compounds.
 63. A compound of the formula:

wherein R₁ is (1) hydrogen, (2) optionally substituted alkyl, (3)optionally substituted alkenyl, (4) optionally substituted alkynyl, (5)optionally substituted cycloalkyl, (6) optionally substitutedcycloalkenyl, where the substituents on the alkyl, alkenyl, alkynyl,cycloalkyl and cycloalkenyl are 1 to 3 groups independently selectedfrom (i) alkyl, (ii) X-alkyl, where X is O or S(O)_(m), (iii)cycloalkyl, (iv) hydroxy, (v) halogen, (vi) cyano, (vii) carboxy, (viii)NY¹Y², where Y¹ and Y² are independently H or alkyl, (ix) alkanoylamino,and (x) aroylamino wherein said aroyl is optionally substituted with 1to 3 groups independently selected from R^(f) (7) aryl or arylalkylwherein said aryl is optionally substituted with 1 to 3 groupsindependently selected from R^(f), (8) perfluoroalkyl (9) a 5- or6-member heterocycle containing from 1 to 4 heteroatoms independentlyselected from oxygen, sulfur and nitrogen atoms optionally substitutedby 1 to 3 groups independently selected from hydroxy, oxo, alkyl andhalogen, and which may be saturated or partly unsaturated, R₂, R₃, andR⁴ are independently OR^(a), OCO₂R^(b), OC(O)NR^(c)R^(d); or R₁ and R₂represent ═O, ═NOR^(a) or ═N—NR^(c)R^(d); R^(a) is (1) hydrogen, (2)optionally substituted alkyl, (3) optionally substituted alkenyl, (4)optionally substituted alkynyl, (5) optionally substituted alkanoyl, (6)optionally substituted alkenoyl, (7) optionally substituted alkynoyl,(8) optionally substituted aroyl, (9) optionally substituted aryl, (10)optionally substituted cycloalkanoyl, (11) optionally substitutedcycloalkenoyl, (12) optionally substituted alkylsulfonyl (13) optionallysubstituted cycloalkyl (14) optionally substituted cycloalkenyl wherethe substituents on the alkyl, alkenyl, alkynyl, alkanoyl, alkenoyl,alkynoyl, aroyl, aryl, cycloalkanoyl, cycloalkenoyl, alkylsulfonyl,cycloalkyl and cycloalkenyl are from 1 to 10 groups independentlyselected from the group consisting of hydroxy, alkoxy, cycloalkyl, arylalkoxy, NR^(g)R^(h), CO₂R^(b), CONR^(c)R^(d) and halogen, (15)perfluoroalkyl, (16) arylsulfonyl optionally substituted with 1 to 3groups independently selected from alkyl, perfluoroalkyl, nitro, halogenand cyano, (17) a 5- or 6-member heterocycle containing 1 to 4heteroatoms selected from oxygen, sulfur and nitrogen optionallysubstituted by 1 to 4 groups independently selected from alkyl, alkenyl,perfluoroalkyl, amino, C(O)NR^(c)R^(d), cyano, CO₂R^(b) and halogen, andwhich may be saturated or partly unsaturated; R^(b) is (1) H, (2)optionally substituted aryl, (3) optionally substituted alkyl, (4)optionally substituted alkenyl, (5) optionally substituted alkynyl, (6)optionally substituted cycloalkyl, (7) optionally substitutedcycloalkenyl, or (8) optionally substituted heterocycle containing from1 to 4 heteroatoms independently selected from oxygen, sulfur andnitrogen; where the substituents on the aryl, alkyl, alkenyl,cycloalkyl, cycloalkenyl, heterocycle, or alkynyl are from 1 to 10groups independently selected from (i) hydroxy, (ii) alkyl, (iii) oxo,(iv) SO₂NR^(g)R^(h), (v) arylalkoxy, (vi) hydroxyalkyl, (vii) alkoxy,(viii) hydroxyalkoxy, (ix) aminoalkoxy, (x) cyano, (xi) mercapto, (xii)alkyl-S(O)_(m), (xiii) cycloalkyl optionally substituted with 1 to 4groups independently selected from R^(e), (xiv) cycloalkenyl, (xv)halogen, (xvi) alkanoyloxy, (xvii) C(O)NR^(g)R^(h), (xviii) CO₂R^(i),(xix) formyl, (xx) —NR^(g)R^(h), (xxi) 5 to 9-member heterocycle, whichmay be saturated or partially unsaturated, containing from 1 to 4heteroatoms independently selected from oxygen, sulfur and nitrogen, andoptionally substituted with 1 to 5 groups independently selected fromR^(e), (xxii) optionally substituted aryl, wherein the aryl substituentsare 1,2-methylenedioxy or 1 to 5 groups independently selected fromR^(e), (xxiii) optionally substituted arylalkoxy, wherein the arylsubstituents are 1,2-methylenedioxy or 1 to 5 groups independentlyselected from R^(e), and (xxiv) perfluoroalkyl; R^(c) and R^(d) areindependently selected from R^(b); or R^(c) and R^(d) together with theN to which they are attached form a 3- to 10-member ring containing 0 to2 additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(g),hydroxy, thioxo and oxo; R^(e) is (1) halogen, (2) alkyl, (3)perfluoroalkyl, (4) —S(O)_(m)R^(i), (5) cyano, (6) nitro, (7)R^(i)O(CH₂)_(v)—, (8) R^(i)CO₂(CH₂)_(v)—, (9) R^(i)OCO(CH₂)_(v)—, (10)optionally substituted aryl where the substituents are from 1 to 3 ofhalogen, alkyl, alkoxy, or hydroxy, (11) SO₂NR^(g)R^(h), or (12) amino;R^(f) is (1) alkyl, (2) X-alkyl, where X is O or S(O)_(m), (3) alkenyl,(4) alkynyl, (5) perfluoroalkyl, (6) NY¹Y², where Y¹ and Y² areindependently H or alkyl, (7) hydroxy, (8) halogen, and (9) alkanoylamino, R^(g) and R^(h) are independently (1) hydrogen, (2) alkyloptionally substituted with hydroxy, amino, or CO₂R^(i) (3) aryloptionally substituted with halogen, 1,2-methylenedioxy, alkoxy, alkylor perfluoroalkyl, (4) arylalkyl, wherein the aryl is optionallysubstituted with perfluorolkyl or 1,2-methylenedioxy; (5)alkoxycarbonyl, (6) alkanoyl, (7) alkanoylalkyl, (9) arylalkoxycarbonyl,(10) aminocarbonyl, (11) monoalkylaminocarbonyl (12)dialkylaminocarbonyl; or R^(g) and R^(h) together with the N to whichthey are attached form a 3- to 7-member ring containing 0 to 2additional heteroatoms selected from O, S(O)_(m), and N, optionallysubstituted with 1 to 3 groups independently selected from R^(e) andoxo; R^(i) is (1) hydrogen, (2) perfluoroalkyl, (3) alkyl, (4)optionally substituted aryl, or arylalkyl, where the aryl substituentsare from 1 to 3 groups independently selected from halogen, alkyl,alkoxy, and hydroxy; m is 0 to 2; and v is 0 to 3; R^(6′) and R^(7′) canbe independently selected from alkyl and cycloalkyl, or a salt thereof.